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Virology Lecture 1
Lecture 2
Lecture 9
Lecture 10
Lecture 11
Lecture 12
Contact :
Dr Richard Hunt
Medical Microbiology
MBIM 650/720 Lectures: 62 and 63
immunodeficiency virus (HIV) is found in all cases of AIDS
(acquired immunodeficiency disease syndrome). In the infected patient,
it can be detected by the presence of anti-HIV antibodies or by the
presence of the virus itself using polymerase chain reaction (PCR). The
latter is very sensitive and can show HIV in situations in which it is not
detectable immunologically.
is a lentivirus, a class of retroviruses, and integrates into the
genome in the same manner as other retroviruses. Unlike other
retroviruses, which typically bud from the infected cell for a long period
of time, HIV can lyze the cell or lie dormant for many years, especially
in resting T4 (CD4) lymphocytes; later, a recrudescence of viral
production occurs that ultimately destroys the cell. It should be noted
that while HIV may disappear from the cells of the circulation, viral
replication and budding continues to occur in other tissues. In contrast
to T4 lymphocytes, other HIV-infected cells do not show a pronounced
cytopathic effect and may exhibit latency or continual budding.
Unlike many other retroviruses, no copies of primate lentiviruses
are found in the genome of target species and the virus not transmitted
through the germ line.
Undifferentiated Non-Hodgkins Lymphoma among Homosexual Males --
United States
The first report of
transfusion-related immune deficiency In December 1982: Possible
Transfusion- Associated Acquired Immune Deficiency Syndrome (AIDS)
First report of
hemophilia-related immune deficiency in July 1982: Pneumocystis
carinii Pneumonia among Persons with Hemophilia A.
In 1981, clusters of
cases of Kaposi's sarcoma were observed in patients in San Francisco and
New York. Kaposi's sarcoma normally occurs in the United States in elderly
men of Jewish or Mediterranean ancestry (Information
Box) but these new clusters of patients were all were young
male homosexuals. Other diseases associated with immuno-compromisation
also occurred in this same population; particularly of note were the
occurrence of Pneumocystis pneumonia (an opportunistic infection)
and lymphadenopathy (Non-Hodgkins lymphoma).
pneumonia, which is caused by an intracellular parasite (Pneumocystis
carinii), was also a very rare disease. During the period between 1967
and 1978, only five cases of this disease occurred in Los Angeles but in
1981 alone, five cases occurred in the same area. Again, all patients were
young male homosexuals. The number of sex partners of these patients
appeared to be important in that the disease was particularly prevalent
among promiscuous individuals and the partners of those individuals.
Later, a similar immunodeficiency was found in intra-venous drug users who
shared needles, persons who received blood transfusions and hemophiliacs.
Moreover, the sex partners of these patients also got the disease. In view
of this, it was obvious that an infectious agent was involved; this agent
was either passed during sexual intercourse or by receiving blood (or
blood products) from another person. The cell picture - the selective loss
of T4 helper (CD4+) cells - suggests a virus. But the causative agent was
difficult to identify at first because it does not grow on resting T4
cells. The discovery of HIV depended on the ability to grow the virus in
The disease was
originally termed Gay-Related Immune Deficiency (GRID) but we now know it
as Acquired Immuno-Deficiency Syndrome (AIDS). AIDS is invariably fatal
(unless chemotherapeutic intervention occurs). The epidemic has resulted
in the deaths of more than half of AIDS patients. Exactly when HIV entered
the human population is unknown (Information
Lesions on the stomach of
a patient with Kaposi's sarcoma
Skin showing AIDS-associated Kaposi's sarcoma
Bristol Biomedical Image Archive, University of Bristol. Used with
3 - Kaposi's Sarcoma
The clue to growing the virus came
with the realization that, while it did not grow on resting T4
lymphocytes, it would grow on T4 cells that had been activated with a
cytokine called interleukin-1. The virus was finally isolated by Luc
Montanier (Pasteur Institute, Paris) and Robert Gallo (NIH, Bethesda,
USA). Montanier called the virus lymphadenopathy virus (LAV)
and Gallo, who had discovered the first human leukemia virus (HTLV-1),
named the virus HTLV-3. Today we know it as human immunodeficiency
virus (HIV).
A similar cellular picture is seen
in some cases of feline leukemia and HTLV-1, i.e. a selective loss of a
specific class of cells giving rise to immune suppression, further
suggesting that the cause of AIDS is a virus.
Course of the disease
From the original infection, there
is usually a period of 8-10 years before the clinical manifestations of
AIDS occur; however, this period may be two years or less. Approximately
10% of patients succumb to AIDS within 2 to 3 years
Acute infection (acute retroviral syndrome)
Initially, HIV
infection produces a mild disease that is self-limiting. This is not
seen in all patients and many remain symptomatic during the initial period
of infection. In the period immediately after infection, virus titer rises
(about 4 to 11 days after infection) and and continues at a high level
over a period of a few weeks. The patient experiences some
mononucleosis-like symptoms (fever, rash, swollen lymph glands (Information
Box)) but none of these are life-threatening. The result is an initial
fall in the number of CD4+ cells and a rise in CD8+
cells but the numbers quickly return to near normal.
b) A
strong cell-mediated and humoral anti-HIV immune defense
Cytotoxic B and T
lymphocytes mount a strong defense and virus largely disappears from the
circulation. During this period, more than 10 billion new HIV particles
are produced each day but they are rapidly cleared by the immune system
and have a half life of only 5-6 hours (some estimates show a half
life of minutes). There can be up to 104 to 107
virus particles per ml of blood. (Titers of infectious virus are much
lower indicating that much of the plasma virus is defective or
neutralized). Most of this virus is coming from recently infected
proliferating CD4+ cells. The infected cells that are producing
this virus are destroyed either by the immune system or by the virus (half
life about 1 day). However, the rate of production of CD4+
cells can compensate for the loss of cells and a steady state is set up in
which a very small fraction of the resting memory CD4+ cells
carry an integrated HIV genome. Most CD4 cells at this stage are
The virus disseminates to other regions including to lymphoid and nervous
tissue. This is the most infectious phase of the disease. Seroconversion
occurs between one and four weeks after infection.
c) A
latent reservoir. As a
result of the strong immune defense, the number of viral particles
in the blood stream declines and the patient enters clinical latency. Little
virus can now be found in the bloodstream or in peripheral blood
lymphocytes. Initially, the number of blood CD4+ cells is only slightly
decreased. Nevertheless, the virus persists elsewhere, particularly
in follicular dendritic cells in lymph nodes and here viral replication
continues. Virus can become trapped in the follicular dendritic cell
network of lymphoid tissue. The virus is also replicated by macrophages. A
small fraction of the productively infected CD4+ cells may
survive long enough to revert back to the resting memory state (as do
non-infected CD4+ memory cells). The resting memory cells do
not express viral antigens but do carry a copy of the HIV genome which
remains latent until the cells are reactivated by antigen. These memory
cells have a great potential for stability and constitute a reservoir that
may be very important in drug-based therapy.
Note: Although the
number of HIV particles in the bloodstream falls during clinical latency,
the virus is detectable. After the initial peak of virus, the virus
reaches a "set point" during latency. This set point predicts
the time of onset of clinical disease. With less than 1000 copies/ml
of blood, disease will probably occur with a latency period of more than
10 years. With less than 200 copies/ml, disease does not appear to
occur at all. Most patients with more than 100,000 copies per ml, lose
their CD4+ cells more rapidly and progress to AIDS before 10 years. Most
patients have between 10,000 and 100,000 copies per ml in the clinical
latency phase (See below).
Loss of CD4+ cells and abortion of the immune response.
One reason that the immune system fails to control HIV infection is that
the CD4+ T helper cells are the target of the virus. Also
follicular dendritic cells can be infected with HIV and these also
diminish in number over time. Moreover, they present antigen to CD4+
cells and may bring the virus into contact with these cells at the time
that they are stimulated to proliferate by antigen.
Note: During the
course of infection, there is a profound loss of the specific immune
response to HIV because:
i) responding CD4+ cells become infected. Thus there is clonal deletion
leading to tolerance. The cells that proliferate to respond to the virus
are infected and killed by it;
ii) epitope variation (see below) can lead to escape of HIV from the
immune response;
iii) activated T cells are susceptible to apoptosis. Spontaneous apoptosis
of uninfected CD4+ and CD8+ T cells occurs in
HIV-infected patients. Also there appears to be specific apoptosis of
HIV-specific CD8+ cells;
iv) the number of follicular dendritic cells falls over time,
resulting in diminished capacity to stimulate CD4+ cells
There is thus a
relentless decline of CD4+ cells with especially a loss of
those specific to HIV. This occurs from the very beginning of infection
and is permanent. Near the end stage of AIDS, CD8+ cells also
decline precipitously. It is nevertheless the case that during the course
of HIV infection, most CD4+ cells are never actually infected by the virus
but die from some other means (see below).
Onset of AIDS. The period
of clinical latency varies in length from as little as 1-2 years to more
than 15 years but, eventually, the virus can no longer be controlled
as helper CD4+ (T4) cells are destroyed. Ironically, the killer cells
needed to control HIV also damage the helper T cells that they need to
function efficiently. With the lack of CD4+ cells, new
cytotoxic T cell responses cannot occur as helper cells are lacking and
such new responses are demanded as the virus mutates. As the T4 cells fall
below 200 per cu mm, virus titers rise rapidly and immune activity drops
to zero. It is the loss of immune competence that enables normally benign
opportunistic parasites such as fungi or protozoa to cause infections.
Once AIDS develops, patients rarely survive more than two years without
chemotherapeutic intervention. (See anti-HIV
chemotherapy section). There is considerable variability at this
stage. Some patients with clinical AIDS do survive for several years while
others who appear relatively healthy can suddenly succumb to a major
opportunistic infection. It is the onset of HIV-associated neoplasms
and opportunistic infections that defines AIDS proper (Information
Box). At this stage, also, syncytium-inducing HIV appear in many
(about half) AIDS patients (see below). These are more CD4+ cell tropic
than the initially infecting HIV and this switch contributes to the rapid
loss of CD4+ cells in later stages of the disease.
Note: A phase of HIV
infection, AIDS-related complex (ARC), used to be defined. This is
now little used. It is the phase of the disease that lacks the neoplasms
and opportunistic infections that are the definition of AIDS. Patients at
this stage of the disease show weight loss and fatigue together with
fungal infections of the mouth, finger and toe nails.
6 - AIDS related diseases
possible co-factors associated with lifestyle, HIV infected persons
progress to AIDS at a remarkably similar rate. The mean time from
seroconversion to onset of disease is approximately 9 years. Perinatally-infected
infants progress faster. Signs of AIDS can be seen by 5 months in more
than 80% of seropositive children. About half die by nine years of age. In
neonates, the level of viral RNA rises rapidly in the first few months of
life but does not decline as rapidly as is seen in adults. The
decline that occurs, takes place over a period of a year or more. This
presumably reflects the less effective infant immune system. As in adults,
the level of HIV RNA predicts the rapidity of progression to AIDS.
There are a variety of
factors that determine progression of an HIV infection to clinical AIDS
disease (Information
Mosquitoes Cannot Transmit the AIDS Virus
load but not CD4+ T cell number is a good indicator of rapid progression
to AIDS
The onset of AIDS
occurs, on average, 10 to 11 years after infection but in the absence of
treatment some individuals progress much faster. About 20% of patients
exhibit AIDS symptoms within 5 years of infection while others remain
disease free much longer than average. The onset of AIDS correlates with
the diminution of the number of CD4+ T cells but the major loss of T cells
occurs late in infection. A marker that could predict the prognosis for
AIDS progression early in the disease would be useful. Not surprisingly,
the initial baseline viral load (that is when the patient is first
monitored for virus number) is a good predictor of the time it will take
for disease to appear. CD4 cell number is not a good predictor.
Relationship between baseline CD4+ T cell number and
progression to AIDS. With the exception of patients who
entered the study with less than 321 CD4+ cells per microliter
of blood, no difference was found in either the time of disease
onset or the time of death among patients with CD4+ cell counts
of 322 to more than 787.
8 - Predictors of progression to AIDS
in AIDS--The enigma of Kaposi's
Kaposi's sarcoma (KS) (Information
Box) is often a corollary of HIV-1 infection in gay men (it is ten
times more frequent in gay or bisexual men with AIDS than in other types
of HIV-infected individuals such as i.v. drug users or hemophiliacs). Over
20% of HIV-infected gay men suffer from KS (in the absence of
chemotherapy) and HIV-positive patients are at 20,000 fold increased risk
of KS compared to general population. Compared to primary
immunodeficiencies without HIV infection, KS develops 300 times more often
in immunocompromised gay men with AIDS.
Clinically, most KS is
so indolent that many affected individuals die of other unrelated causes.
However, the AIDS-associated form is more progressive involving many sites
(skin, lymph nodes, lungs, intestine). This form of Kaposi's sarcoma, so
typical of the progression of AIDS in gay men, is not found in other
populations that are HIV-positive. It has long been suspected, therefore,
that Kaposi's is not the direct result of HIV but some co-factor that is
activated in the presence of HIV. This now seems to be the case. In 1994,
a Kaposi's sarcoma-associated herpes virus (KSHV, now known as human
herpes virus-8 (HHV-8)) was identified. It is found in all KS lesions
and in all forms of KS. In AIDS patients, antibodies against KSHV are
common only in those that have KS or those that will eventually get KS
(greater than 80% of this population - in fact detection of KSHV in
asymptomatic HIV-infected patients strongly predicts subsequent
progression to KS). In contrast, blood samples from infected hemophiliacs
show no anti-KSHV antibodies. (Statistics
Information Box)
It is not known why
the virus has established itself to a relatively large extent in the gay
population when most herpes viruses are widely disseminated throughout the
population. Clearly, however, KSHV is sexually transmitted.
AIDS is currently
defined in persons older than 13 years as the presence of one of 25
conditions indicative of severe immunosuppression (Information
Box) or HIV infection in an individual with a CD4+ cell
count of <200 cells per cubic mm of blood. AIDS is therefore the
end point of an infection that is continuous, progressive and pathogenic.
With the prevalence of HIV in the developing world, HIV and its
complications will be with us for generations. AIDS is now a leading cause
of death worldwide.
Approximately 8500 new
HIV infections occur daily around the world and over 90% of these are in
developing countries. One thousand are in children less than 15 years of
age. Of adult infections, 40% are in women and 15% in individuals of 15-25
years of age. Perinatal infection is now resulting in a large number of
children being born with HIV. 30-50% of mother to child transmissions of
HIV results from breast feeding and about a quarter of babies born to
HIV-infected mothers are themselves infected.
United States
Statistics from Centers for Disease Control
As of June 2000,
753,907 Americans had been reported with AIDS (up from 641,086 in 1996).
At least 438,795 of them have died. In early years of the epidemic, AIDS
incidence increased by 65-95% each year but partly as a result of
prevention efforts targeting those at highest risk, the rate of increase
fell to less than 5% per year by the mid 1990's. This was prior to the
introduction of combination therapies for HIV. In 1996, estimated
AIDS incidence dropped for the first time, declining 6%. Deaths among
people with AIDS also declined for the first time in 1996, dropping 25% (Information
Box) (More
At the end of 2000, an
estimated 322,865 people were living with AIDS in the United States (up
from 242,000 in 1996); however, the number of new cases diagnosed has
steadily fallen in recent years (Information
Note: As more and more
people survive with an HIV infection because of successful
chemotherapeutic intervention, the number of infectious people in the
population is rising even though fewer people are dying of AIDS. Thus,
if declines in AIDS deaths continue, there will also be an increase in HIV
prevalence, pointing to an increased need for both prevention and
treatment services.
CASES OF AIDS IN THE US (by age)
# of AIDS
CASES (June 2000)
Under 5:
Ages 5 to
Ages 13
to 19:
Ages 20
to 24:
Ages 25
to 29:
Ages 30
to 34:
Ages 35
to 39:
Ages 40
to 44:
Ages 45
to 49:
Ages 50
to 54:
Ages 55
to 59:
Ages 60
to 64:
Ages 65
or older:
World Statistics
from The World Health Organization/UNAIDS
Go here
for more data on AIDS and HIV prevalence UNAIDS
In Africa
(mostly sub Saharan), there are more than 24 million people with HIV
infection and about 1 million new cases of AIDS per year (Information
Box). In 1996, South East Asia had 183,000 new cases and 5.2 million
people with HIV. (For further global figures, go
AIDS is responsible
for a decrease in life expectancy and increase in child mortality. Child
mortality rates in East Africa will double by 2010 and adult life
expectancy has already declined by 2 years in that region. (Information
HIV infections have
leveled off in the west and the wave of infections threatening to affect
western heterosexuals has not materialized. However, this is not the case
elsewhere and there have been huge increases in southern Asia and southern
Several countries in
sub-Saharan Africa report infection rates of 20%, especially in urban
areas. In some Kenyan and Zambian towns, 1 in 5 girls is
HIV-positive by the age of 20 (Information
Box). In men over 25, the percentage who are HIV-infected can be as
high as 40%. In Botswana, the proportion of the adult population
living with HIV has more than doubled over the last five years, with 43%
of pregnant women testing HIV-positive in 1997 in the major urban center
of Francistown. In Zimbabwe, one in four adults in 1997 were thought to be
Current estimates are
that more than 34 million people had an HIV infection at the beginning of
the year 2000 (for the present number go here)
For UNAIDS/WHO report (2000)
on HIV/AIDS statistics go
here (requires Acrobat)
It is likely that other factors
than the presence of HIV influence the course of the disease but there is
no strong evidence that there is any other specific infecting agent than
HIV in AIDS (Please see appendix
2 for further details).
cuts life expectancy in sub-Saharan Africa by a quarter (Requires
Two types of HIV can
be distinguished genetically and antigenically. HIV-1 is the cause of the
current pandemic while HIV-2 is found in west Africa but rarely elsewhere.
It causes AIDS much more slowly than HIV-1. The HIV-2 type is closely
related to simian immunodeficiency virus (SIV) found in west Africa. There
are also 10 different HIV-1 subtypes. The major one in the US and Europe
is type B. In some countries, mosaics between different subtypes have been
non-progressors and exposed-uninfected individuals
Ever since the AIDS
epidemic began there have been people who are clearly exposed to the virus
but who seem to exhibit no symptoms and normal CD4+ T cell
counts. These are called long term non-progressors: People
who have been infected with HIV for more than 7 years, who have stable CD4+
T cell counts above 600 per cu mm and have no history of symptoms and have
not been taking anti-retroviral drugs. Their lymph node structure seems
The CD4+ T
lymphocytes of these patients fall after primary infection and
seroconversion but remain at normal levels thereafter, in some cases up to
15 years. This seems to be a heterogeneous group of people whose long-term
non-progressive disease results from a robust CD8+ T cell immune response
against HIV, a poorly replicative virus, or mutations in co-receptors that
HIV needs, along with CD4 antigen, to enter the cell.
and disease
As noted below (see
section on co-receptors), a chemokine receptor on the surface of
macrophages and activated T helper CD4+ cells was targeted by
researchers as a co-receptor for HIV because of its known binding to three
chemokines which seem to block infection. The nature of this co-receptor
may be one explanation of the people who are exposed repeatedly to HIV but
remain uninfected. It has been found that the cells of some non-progressors
are very resistant to HIV infection because they have mutant chemokine
receptors. The most common of these is a 32 base pair deletion that
prevents surface expression of a chemokine receptor known as CCR5.
CCR5 mutations are
relatively rare. If 2 copies of the gene for CCR5 are defective, it is
virtually impossible for virus to enter the cell and exposed patients are
immune from HIV infection. Approximately 1 in 100 Caucasians have this
double mutation. 17% have single defective gene. No African-Americans have
so far been found with a double mutation but about 2% have single
mutation. A single defective gene does not confer resistance but progress
to disease is much less rapid. It is surprising that these people do not
seem to have a reduced viral load or higher CD4 counts so the reason why
these people progress better is unclear!
There are many of
these chemokine receptors and some others are likely to be HIV
co-receptors. A heterozygous mutation in CCR2 may defer AIDS by an
average of 2 to 4 years. This protective CCR2 mutation is present in all
races in the U.S. at a frequency of about 20-25%. One quarter of long term
survivors are CCR2 or CCR5 mutants
Other long term non-progressors
appear to make elevated levels of the chemokines that bind to these
receptors and perhaps this keeps the receptor blocked. This might lead to
therapy in which the chemokine receptors of macrophages and T-cells are
blockaded - as noted below, some chemokines are powerful suppressors of
HIV infection in vitro.
antigens and disease
There are other
suggestions concerning exposed-uninfected individuals. A study of Nairobi
prostitutes, repeatedly exposed to HIV (25% or more of their clients are
HIV positive), has shown that many of these women have been free of
disease for more than 12 years and seem to be completely resistant to
infection. There seem to be associations between their resistance to
infection and their class I and class II MHC (HLA) haplotypes. The
strongest association of protection is with HLA-A*6802, A*0202 and B18.
These women have mounted a very strong CTL response that is likely
to mediate protection. It is possible that these particular class I
MHC antigens allow a very efficient CTL response. Alternatively,
they may present epitopes that are highly conserved between different
HIV-1 variant strains. For example, one epitope to which there is a strong
CTL response in these women is that presented by B18. This epitope is
found to be located in a highly conserved part of HIV p24 protein. It
appears to be conserved because it is very important in the assembly of
the virus. Another important epitope is presented by HLA-A*6802 and this
is in the protease. The protease may not be able to bear much
mutation in this region without losing enzymic activity and so the virus
cannot escape the immune response by mutation.
of HIV
HIV is a retrovirus
with a similar structure to other retroviruses.
14 - HIV structure
membrane: This is host-derived as a result of budding from the
cell surface. Some host proteins become incorporated into the viral
Surface glycoprotein:
Gp160 is encoded by the env (envelope) gene. Gp160 is
cleaved after translation by host enzymes in the Golgi Body to form Gp120
(SU) and Gp41 (TM). Gp 41 is embedded in the membrane, Gp120 is not but is
held to Gp41 by non-covalent interactions. It is easily shed from the
virus particle. Note: Gp120 and Gp41 are made from a single polypeptide.
There is a large number of sugar chains on gp120 (which may pose
a problem for a vaccine). Gp120 is the protein that interacts with a
receptor on the cell to be infected. Gp41 is the fusogen that is exposed
after Gp120 has bound to the cell.
Internal structural
proteins: These are all
encoded by the gag (group-specific antigen) gene. P17 lines the
inner surface of viral membrane to which it is attached by covalently
bound myristic acid. Other proteins associated with the nucleocapsid
include p24 and p9. The group-specific antigen is made as a polyprotein
and is cleaved after budding of the virus by a virally-encoded protease
encoded by the pol gene.
Other internal
proteins: These are
encoded by the pol (polymerase) gene. They are enzymes
that participate in integration and replication: reverse transcriptase,
integrase, protease.
Like other retroviruses, the genome is diploid positive sense RNA
history of HIV
that are infected by HIV
helper lymphocytes are the most studied but monocytes/macrophages are
also infected and may provide an important reservoir. HIV also infects
oligodendrocytes, astrocytes, neurones, glial cells. The virus lyzes T4
cells specifically, causing profound immuno-suppression. Other cells
tend to harbor the virus without lysis.
Follicular dendritic
cells (FDCs) may also be involved. When virus enters the healthy lymph
node, it is trapped by FDCs so that when T cells reach this region of the
body (approx 20% of an individual's T cells go through this area daily),
many are infected. Thus, FDCs serve as a reservoir for further infection.
antigen is the HIV receptor
The apparent
specificity of CD4+ cell infection observed initially,
together with the observation that T4 cells are those that are depleted in
disease (indeed, the course of disease in the patient is followed by CD4+
cell levels), suggested that CD4 antigen might be the receptor for the
virus. This was demonstrated by transfecting the CD4 antigen gene into CD4-
human cells (such as HeLa cells) and showing that they acquired the
property of being able to be infected by HIV.
A co-receptor for infection by HIV
However, something
more appears to be necessary as this experiment only works with human
cells; for example, mouse cells transfected with the CD4 antigen gene are
not infected by HIV.
It was also discovered
that some strains of HIV (those adapted for life in transformed T cells)
could replicate in activated human T cells but not in monocytes or
macrophages. Conversely, those adapted for life in macrophages could not
replicate in transformed T cells. Yet both macrophages and T4 cells
possess CD4 antigen. The differences in tropism of the viral strains
mapped to the V3 region of Gp120 suggesting that molecules other than CD4
antigen have an important role in binding and this role is CD4+
cell type-specific.
receptors seem to be the key to the gateway of the cell-- a family of
proteins on the surface of immune cells
Several laboratories identified an essential co-receptor for those HIV
strains involved in critical early stages of infection (these are
the macrophage-tropic strains). All of these studies found CCR5 as the
partner of CD4 in allowing entry into macrophages.
The discovery of this
molecule as the co-receptor came from previous studies that showed that
three chemokines secreted by CD8+ T lymphocytes (called RANTES,
MIP-1a and MIP-1b), which are involved in inflammatory responses, are
powerful suppressors of HIV infection, and especially macrophage-tropic
HIV. Of course, this suggested that the suppression of infection might be
because the chemokines bound to the cell surface and blocked a receptor
that HIV needed for entry. Suspicion fell on CCR5 because it was known to
be the receptor that binds all three of the above chemokines.
(also known as fusin) is
also a co-receptor for HIV in otherwise non-infectable CD4+ cells. CXCR4
is a G protein-coupled receptor whose ligand is a B cell stimulatory
factor--it is called fusin because it promotes the infection/fusion of
CD4+ cells. The amount of fusin on the cell surface may explain
differences in tropism and fusin seems to be more active in T cells than
in macrophages. Note the fusin gene most closely resembles the gene for
IL-8 receptor (also a chemokine receptor)
Another co-receptor
(CCR2) has also been found.
Complexes of pieces of
CD4 and Gp120 also bind to CCR5 on CD4- cells. This explains
why soluble CD4 actually enhances HIV infectivity and does not block it.
It seems that Gp120 binds CD4 and undergoes a conformational change that
increases its affinity for the chemokine receptor. The binding of the
chemokine receptor causes a conformational change in the gp41 fusion
protein of HIV that allows fusion of the viral membrane with the membrane
of the cell to be infected. In fact, it is really the chemokine receptor
that is the primary receptor for HIV and the role of CD4 is to concentrate
virus at the cell surface and facilitate interaction with the chemokine
receptor. In contrast to examples of CD4-independent HIV entry into cells,
there are (so far) no examples of entry independent of chemokine
These co-receptors may
explain the phenotypic switch during infection (see below). Changes in the
amino acid sequence of Gp120 occur in the progression of the disease. It
is likely that HIV uses CCR5 in the early stages of disease and then
switches to CXCR4 perhaps avoiding the suppressive activity of chemokines.
This also explains the transition from non-syncytium-inducing to syncytium
inducing phenotype. Note: CXCR4 and CCR5 are members of a very large
family (thousands) of receptors and the spread of HIV through subtypes of
T cells may reflect subtle changes on the variable loops of Gp120 allowing
the infection of new CD4+ cells with different receptors. This
may also be one reason why so few CD4+ cells appear to be
infected at any one time. (Information
PowerPoint slides of
the entry of HIV (go
Shockwave movie of
entry of HIV (go here)
Requires Shockwave plug-in
CD4-negative cells can be infected by HIV
It was originally
thought that only cells that have CD4 antigen are infected. Although CD4
protein had not been demonstrated on some infectable cells, it was thought
to be present in low amounts and the mRNA could be detected in most
infectable cells. Specificity to CD4 positive cells reflects the specific
binding of Gp120 to CD4. It is now known, however, that some non-CD4
cells, such as those in brain and intestine, can be infected in a via a
galactocerebroside receptor. Other cells can be infected in a different
way; for example, in macrophages (see below) an Fc or complement receptor
may be used. In these cases, the HIV must be bound by anti-HIV antibodies
that interact with receptors on the cell surface. Thus anything that can
up-regulate Fc receptors on macrophages will augment infection.
into cell: pH-independent
fusion with plasma membrane.
No pH-dependent
conformational change in a viral membrane protein is necessary for fusion
between the viral membrane and the membrane of the cell to be infected.
Thus, no entry into lysosomes is required.
Remember from the
section on herpes virus: This sort of fusion of virus with the plasma
membrane is associated with fusions of infected cells to form syncytia.
Syncytium formation is also a characteristic of HIV infection. This has
profound significance for spread of infection between cells without
any free virus. This means that virus may spread from cell to cell so that
immune system circulatory antibodies cannot have any effect (problem
for vaccine). Not only will a vaccine have to be able to destroy the
virus, it will also have to be able to destroy infected cells. Gp41 is the
fusogen. Syncytia are most often seen in brain.
Reverse transcription and integration This is
similar to other retroviruses. HIV uses reverse transcriptase imported
during infection as part of the virus.
of polyproteins and their cleavage:
Assembly of new
virus takes place at the membrane of the host cell. Three types of protein
make up the virion. These are the membrane protein complex (Gp120 and Gp41
- originally derived from Gp160) plus two internal precursor proteins, the
GAG polyprotein and the GAG/POL polyprotein (the latter is the result of a
frame shift that allows the ribosome to continue translation from the GAG
gene into the POL gene)
The proteins aggregate
at the cell membrane and the membrane pinches off. The larger internal
precursor draws two strands of the positive strand RNA into the nascent
virion and the protease (part of the larger internal precursor protein)
cuts itself free
protease completes the cleavage of the larger internal precursor to
liberate other enzymes (reverse transcriptase, integrase and more
protease). The protease cleaves the remainder of the larger internal
precursor and the smaller internal precursor into structural proteins.
p24, p7 and p9 form the bullet-shaped core
Note: The GAG and GAG/POL
fusion proteins are made in ratio of about 20:1. After the virus has
budded from the cell, the protease cuts itself free and cuts up the rest
of the proteins in GAG or GAG/POL, releasing the various structural
proteins and reverse transcriptase. This specific protease is vital
as the viral proteins are not functional unless separated. This specific
HIV protease has become a good candidate for a site for an anti-HIV drug
(see below and chemotherapy
notes). GAG/POL and GAG are attached to the viral membrane via a fatty
acid that is covalently bound. The cleavages result in p17 remaining
attached to the membrane. Note gp160 is cut to gp120 and gp41 by a host
enzyme in the Golgi apparatus since it gets to the cell membrane via
the exocytic pathway.
lymphocytes replicate HIV only when they are activated by contact
with an antigen at which time they produce prodigious amounts of virus
that lead to cell lysis and cell death. Thus a variety of viral and
bacterial infections (and unfortunately vaccinations) can markedly
increase HIV load in plasma. Although most infected activated CD4+ cells
are rapidly killed by the virus, they are initially replaced. In contrast,
resting T cells cannot replicate the virus fully and the virus only goes
as far as the pre-integration complex. Although activation of infected
cells leads most often to cell death, the virus can become dormant again
when a small proportion of these cells revert back to the resting memory
state which continues until the cell is once again activated. This
dormancy of the virus in resting memory state cells is referred to as cellular
latency and may last for a few hours or days or very much longer in a
very small minority of cells. Recently, it had been hoped that the used of
highly active anti-retroviral therapies (HAART) would eliminate the
virus from the patient altogether but this minority of resting cells may
provide a reservoir of integrated virus that cannot be eliminated by
In contrast to T4 CD4+
lymphocytes, macrophages do not show latency. They bud virus all the time.
Most viruses that
replicate in the nucleus can do so only in dividing cells but cell
division is not essential for HIV replication. This is because two
viral proteins (Vpr and one of the GAG proteins) have nuclear localization
signals and so nuclear membrane breakdown at mitosis, which allows
penetration of viral DNA to the chromosomes, is not necessary.
Cellular latency is
a different phenomenon from clinical latency which refers to fact
that symptoms of HIV infection do not manifest themselves as AIDS for many
Since HIV has a more
complex life cycle that simple retroviruses such as RSV and it appears
that HIV can control its replication in a more complex fashion, we might
expect more genetic information but this is not so.
HIV genome is 9749
nucleotides-- about the same size as any other retrovirus, for example
Rous sarcoma virus (RSV).
The genome of HIV is
more complex than RSV, however, since it has extra open reading frames
that clearly code for small proteins. Some of these are protein
synthesis-controlling proteins.
The HIV genome has nine open
reading frames but 15 proteins are made in all
The GAG gene and
the GAG and POL genes together are translated into large polyproteins
which are then cleaved by a virus-encoded protease that is part of the POL
GAG polyprotein is cleaved to into four proteins that are found in
the mature virus: MA (matrix) (Information
Box), CA (capsid) (Information
Box), NC (nucleocapsid) (Information
Box), p6 (Information
POL polyprotein is cleaved to: PR (protease) (Information
Box) , RT (reverse transcriptase) (Information
Box) , IN (integrase) (Information
ENV gene is translated to a polyprotein (Gp160) which is then cleaved by a
host cell protease that is found in the Golgi Body.
Gp160 is cleaved to: SU (Gp120) and
TM (Gp41) (Information
In a addition to the nine protein
derived from GAG, POL and ENV, there are six other proteins made by
HIV. Three of these are incorporated into the virus (Vif, Vpr and
Nef) while the others are not found in the mature virus: Tat and Rev are
regulatory proteins and Vpu indirectly assists in assembly. The genes that
encode these proteins are known by three letter names that are derived as
TAT: Trans-Activator
of Transcription
REV: Regulator
of Virion protein expression
NEF: Negative
Regulatory Factor
VIF: Virion
Infectivity Factor
VPU: Viral
Protein U
VPR: Viral
Protein R
These genes encode
small proteins. They overlap with the structural genes (especially ENV)
but are in different reading frames. From the above diagram of the
organization of the HIV genome, it can be seen that some are encoded
in two exons (unlike the structural genes) and therefore their mRNAs can
be derived by alternative splicing of structural gene mRNAs. This is
rather important to the way in which the levels of these are controlled.
Mutants in the TAT and REV genes show that their proteins are both
necessary for virus production.
TAT (Information
TAT gene product binds
to a sequence in all of the genes of HIV and positively stimulates
transcription. It is thus a positive regulator of protein synthesis,
including its own synthesis.
REV (Information
REV binds to an
element only in the mRNA for structural proteins (GAG/POL/ENV) and
regulates the ratio of GAG/POL/ENV to non-structural, controlling protein
(TAT/REV) synthesis. When REV levels are high, structural protein
synthesis rises and controlling protein synthesis falls. Thus REV inhibits
its own production and that of TAT.
The normal result is homeostasis,
low or non-existent virus production and latency in the resting CD4 cell.
There is an inherent
problem in HIV's lifestyle. It uses genomic RNA as its messenger
RNA. This RNA is unspliced and the nucleus has a mechanism to prevent
unspliced mRNAs from leaving the nucleus and being translated. It is the
function of Rev to overcome this problem.
NEF (Information
Nef protein is
synthesized early in infection. Despite its small size NEF has several
a) Homeostasis leads
to problems for the parasitic provirus:
i) Super-infection
by other HIV particles which bind to surface CD4 antigen of the infected
cell may kill the cell.
ii) Probably more importantly, virus bound via CD4 antigen at the cell
surface or free Gp120 bound to CD4 antigen at the cell surface may
result in the cell being subject to an immune attack and the infected
cell may be destroyed.
NEF effects on CD4
i) Super-infection
by other HIV particles which bind to surface CD4 antigen of the infected
cell may kill the cell.
ii) Probably more importantly, virus bound via CD4 antigen at the cell
surface or free Gp120 bound to CD4 antigen at the cell surface may
result in the cell being subject to an immune attack and the infected
cell may be destroyed.
The translation of the
NEF gene as a result of the first infecting virus causes the
internalization of CD4 antigen from the cell surface and its destruction
in lysosomes. Thus no more HIV or gp120 can bind to the surface of an
infected cell!
b) By a different
mechanism from its down regulation of CD4 antigen, NEF reduces surface
expression of MHC class I molecules. This alters antigen presentation by
the infected cell and is proposed to protect the infected cell from attack
by cytotoxic T cells
c) The name, NEF,
comes from negative factor. Originally, it seemed that virions that lacked
NEF grew better than wild type. Now the consensus is for the opposite,
that is that virus produced in the presence of NEF is a little more
infectious than virus produced in its absence.
d) It is found that
NEF is important for HIV replication in vivo but there seems to be
much less effect of NEF in an in vitro cell culture situation. Why
this is so has long been obscure. Recently, this question seems to have
been solved. The answer is found in the macrophages which are changed in
two ways when they are infected with a NEF-expressing HIV (remember that
macrophages are the cells that bring HIV into the body and the initial
strains of HIV in an infected patient are macrophage-tropic).
macrophages secrete MIP-1alpha and MIP-1beta. These are two chemokines
that bind to the co-receptors for HIV infection of macrophages but
here these chemokines have another function.
NEF induces cytokines that attract T cells to an infected
They cause resting
CD4+ T cells to migrate (undergo chemotaxis) towards the infected
macrophages. This is important in vivo since, initially,
HIV-infected cells are not very numerous and uninfected T cells may not
be in the vicinity of the infected cells. Moreover, HIV does not have a
very long half life in the circulation before becoming non-infectious.
Migration of uninfected cells towards infected cells increases the
probability that the T cells will encounter infected macrophages before
they leave the reticuloendothelial system. This explains why NEF
seems not to be of much consequence in cell culture where the cells are
already close together. The infected macrophages do something else. They
make a factor that has not yet been identified that activates the
resting T cells that have been attracted towards them allowing the T
cells to be productively infected and to shed new virus (Remember,
lentiviruses, unlike most other retroviruses can infect non-dividing
cells. Normally, retroviruses can only enter the nucleus and integrate
during mitosis when the nuclear membrane is broken down; however,
proteins of lentviruses such as HIV have nuclear targeting signals that
allow the nucleocapsid to find the nuclear pore. Thus, the virus can
integrate into the host cell chromosome where it can now code for more
viral RNA and protein. HIV, unlike some other lentiviruses, does not
transcribe its genome to RNA in resting T cells since the activation of
the promotor in the LTR requires transcription factors that are only
made when a resting T cell becomes activated). These finding
explain why macrophages are vital for the spread of HIV.
Note: In vivo, HIV can infect a resting T cell but cannot replicate in
that cell. Although NEF can activate the cell, it cannot be made in the
resting T cell. The above observations solve this conundrum. Macrophages
are infected by HIV and make NEF without any activation process. As
a result they make factors that activate resting T cells that can now
support a productive infection!
macrophages secrete MIP-1alpha and MIP-1beta. These are two chemokines
that bind to the co-receptors for HIV infection of macrophages but
here these chemokines have another function.
They cause resting
CD4+ T cells to migrate (undergo chemotaxis) towards the infected
macrophages. This is important in vivo since, initially,
HIV-infected cells are not very numerous and uninfected T cells may not
be in the vicinity of the infected cells. Moreover, HIV does not have a
very long half life in the circulation before becoming non-infectious.
Migration of uninfected cells towards infected cells increases the
probability that the T cells will encounter infected macrophages before
they leave the reticuloendothelial system. This explains why NEF
seems not to be of much consequence in cell culture where the cells are
already close together. The infected macrophages do something else. They
make a factor that has not yet been identified that activates the
resting T cells that have been attracted towards them allowing the T
cells to be productively infected and to shed new virus (Remember,
lentiviruses, unlike most other retroviruses can infect non-dividing
cells. Normally, retroviruses can only enter the nucleus and integrate
during mitosis when the nuclear membrane is broken down; however,
proteins of lentviruses such as HIV have nuclear targeting signals that
allow the nucleocapsid to find the nuclear pore. Thus, the virus can
integrate into the host cell chromosome where it can now code for more
viral RNA and protein. HIV, unlike some other lentiviruses, does not
transcribe its genome to RNA in resting T cells since the activation of
the promotor in the LTR requires transcription factors that are only
made when a resting T cell becomes activated). These finding
explain why macrophages are vital for the spread of HIV.
Note: In vivo, HIV can infect a resting T cell but cannot replicate in
that cell. Although NEF can activate the cell, it cannot be made in the
resting T cell. The above observations solve this conundrum. Macrophages
are infected by HIV and make NEF without any activation process. As
a result they make factors that activate resting T cells that can now
support a productive infection!
After activation of
the T cell, the virus faces another problem: CD4 antigen and Gp120 are
being made in the endoplasmic reticulum of the same cell. They are likely
to bind to one another before reaching the plasma membrane and such
complexes are usually targeted by the cell for degradation. To stop this
unfortunate state of affairs, another of the small HIV proteins (VPU)
promotes the proteolysis of the CD4 antigen of the host cell as it is
also Vif (Information
Box), Vpr (Information
HIV Gene Kills All Tumors In Lab Tests (Vpr)
Latency is broken when
the virus starts to proliferate and this seems to occur when the CD4 cell
is stimulated during an antigenic response. How does this occur? One
factor known to be involved is nuclear factor NF kappa B (NFkB, for short)
which is a transcription factor.
When a lymphocyte is
stimulated by an antigen or by a cytokine binding to a surface receptor,
it responds by proliferating. The signal to grow is relayed from the cell
surface to the nucleus by signaling proteins among which are transcription
factors of which NFkB is one. The NFkB binds to a site in the promotor
region of the genes that are specifically activated during an immune
response. The VERY SAME sequences are found in the HIV LTR!
Why, when only 1 in
10,000 (early) or 1 in 40 (later) cells show productive infection, do all
of the T4 cells disappear? It is still unclear why the CD4+
cells all disappear but there are a number of possibilities:
24 - Some possible mechanism for the loss of T4 cells after HIV
a) In an
activated, infected CD4 cell, huge numbers of virions are synthesized.
These bud from the cell and punctured membranes result. But the cell needs
to be infected for this to happen and most CD4 cells are not infected.
b) Since the
membrane of HIV fuses with the membrane of the cell to be infected by a
pH-independent mechanism, syncytia formation can occur leading to the
spread of virus to uninfected cells. But syncytia are not very common.
c) Infected
cell that are producing viral proteins (but not those in the latent state)
will present those proteins on the cell surface in association with class
I MHC histocompatibility antigens. The infected cell, like other
virally-infected cells will be destroyed by cytotoxic T cells. Again this
only happens in cells that are infected by HIV
d) Gp120 is linked to
the Gp41 on the virus surface by non-covalent interactions and is
frequently shed from infected cells or from virus particles. This binds to
uninfected cells via CD4 antigen. As a result, they appear to be infected
and destroyed by the immune system.
e) There have been
reports of AIDS-related cytotoxic antibodies in infected patients that may
react with a specific antigen on the surface of activated but uninfected
T4 cells.
f) AIDS may have an
auto-immune component. In a normal antigenic response carried out by T4
cells, CD4 antigen interacts with MHC type II histocompatibility antigens.
Since Gp120 also binds to CD4, the Gp120 can mimic MHC class II antigens
since both will have a CD4 binding site; indeed, there appear to be
regions of similar sequence in the two proteins. Thus anti-Gp120
antibodies may turn out to be anti-MHC antibodies as well. (This might
spell trouble for vaccine production).
g) It is possible that
HIV might infect a subset of T4 cells that is vital to propagation
of entire population of T4 cells
h) HIV proteins may
alter T4 cell function. There is some evidence for this.
i) Presently,
the most actively studied possibility for the loss of the entire CD4+ and
CD8+ cell population is that HIV initiates apoptosis in these cells (Such
apoptosis is a normal process in T4 cells to overcome autoimmunity
and to terminate an immune response). This is now thought to be a
major factor in the loss of CD4 cells during the progression of the
disease (Information
Some of the above may
explain why only a minority of T4 cells appear to be infected at a given
time yet all disappear in the later stages of the disease. It could also
be that the virus switches from one T4 cell population to another as it
switches its co-receptor (see above).
cells are not infected by HIV (because they do not have the CD4 receptor)
and their numbers remain high during the course of the disease for many
years. And then, until recently inexplicably, they rapidly die off.
It appears that some of the HIV subtypes that occur late in infection
prompt a mass apoptosis of CD8 cells. Although CD8 cells are CD4-,
they do have CXCR4 co-receptor and HIV can bind to this (only the later
syncytium-inducing strains of HIV do this). Since no CD4 antigen is
present there is no infection but binding to CXCR4 does send a signal to
the cell, the signal for apoptosis and mass CD8+ cell suicide
ensues. It is interesting that the CD8 cells only die when macrophages are
How does this happen?
It is now known that binding of strains of HIV that arise later in
infection to the CXCR4 receptor sets in motion the tumor necrosis-alpha
death transducing pathway (Information
25 - Induction of apoptosis in T8 cells
In macrophages,
binding of a ligand to CXCR4 receptor on the cell surface induces the
expression of TNF-alpha. In CD8+ T cells, the same binding triggers the
expression of TNF-alpha receptor II.
When such a macrophage
and CD8+ T cell come in contact, the TNF-alpha on the macrophage binds to
the receptor on the CD8+ T cell. This triggers an apoptosis signal
in the CD8+ T cell resulting in the vesiculation of the CD8+ T cell.
Macrophages then
phagocytose the remains of the T cell. This explains why macrophages have
to be present for the CD8+ cells to die. Why would this happen naturally?
Why do chemokines act as death signals for CD8+ T cells? These cells are
killer cells and may cause serious trouble if they end up in the wrong
place. It is thought that chemokines direct CD8+ T cells to the fate of
macrophage-mediated death unless they reach their appropriate location.
Although CD4+
T4 cells are usually considered to be the most important cells in the
course of AIDS and it is their loss that leads to immune suppression,
other cells do become infected. Macrophages are very important as they
form a reservoir outside the blood and carry the virus into extravascular
tissues. Non-proliferating mature macrophages can support HIV production
for a long time without being killed. There is no latency in these cells,
the virus just buds. Cytokine production by the infected macrophages is
also aberrant leading to a variety of secondary effects. The slim
disease that is characteristic of HIV infections in Africa may result
from macrophage cytokine disruption. This wasting is very reminiscent of
Visna in sheep and Visna infections involve the macrophages. Macrophages
and macrophage-like cells are infected via CD4 antigen. Also since the
virus raises good antibodies in the host, cells that express Fc or
complement receptors will take up the virus.
Some CD4-negative
cells become infected; for example, epithelial cells of the vagina and
rectum, endothelial cells of brain capillaries and other cells of the CNS.
These may take up HIV via a galactocerebroside receptor. Dendritic cells
may also be very important. These cells appear to trap virions and when
the virus disappears from blood stream the dendritic cells of the lymph
nodes may be the major site of the virus.
polymorphism results from the high error rates of reverse transcriptase
and RNA polmerase II which are used to replicate the viral genome. The
error rate is 1 in 2000-10,000 nucleotides. This together with the high
rate of CD4+ cell production and infection means that every
possible single point mutation in the viral genome arises daily and almost
1% of all possible double mutations occur each day. As a result, the virus
isolated from an AIDS patient is very different from the original
infecting virus. Distinct sub-strains differ in cell tropism. Some form
syncytia, some do not. The non-syncytium-inducing macrophage-tropic
type is probably the infectious form (Note: most vaccines have been
made against the syncytium-inducing form of HIV-1 and polymorphism poses a
great obstacle to the successful development of a vaccine). The major
variable protein is Gp120 and, within a single patient, HIV-1 commonly
varies by 1-6% in the ENV gen. There are some
conserved sites in Gp120 in which mutations are presumably
non-viable (e.g. CD4 binding site). But very often glycosylation masks
these conserved sites (which also poses a problem for vaccine
development). Gp41 is not so glycosylated and the fusion site needs to
be conserved (this may be a possible vaccine site).
Compared to variation
within an individual, there is a lot greater variability around the world.
HIV-1 genetic subtypes differ by up to 30% in the amino acid sequence of
the ENV gene. There are at least 10 subtypes of HIV-1.
Not only is the
reverse transcriptase mutation rate a problem. It is possible to be
infected by different HIV-1 subtypes resulting in cells becoming
co-infected. Resultant viruses have one RNA from one subtype and one from
the other. On later rounds of infection recombination occurs. It has been
found that a recombinant subtype (HIV-1E) is spreading globally. The
impact of these evolving subtypes is great since they may affect the
efficacy of tests for infected blood. Moreover, they have to be taken into
account when thinking of a vaccine. There is also the possibility that
there may be significant differences in the transmissibility of different
subtypes (HIV-1 is much more transmissible than HIV-2)
Most anti-HIV drugs are toxic. In addition, present anti-HIV chemotherapy
does not stop infection and is unlikely to cure the infected host (though
see chemotherapy
lecture notes). The most we can hope for is suppression of virion
production making AIDS a more tractable disease. Recently great strides
towards this goal have made (Please see appendix
HIV is (fortunately) not highly infectious. It can be avoided by taking
the correct precautions. This approach has been very successful in certain
countries in containing their AIDS epidemics.
This is the best way to protect against infection. But HIV is a
retrovirus and this poses enormous problems for vaccine development. (Please
see appendix 1)
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text:
Edit Article
wikiHow to Sew a Pencil Case
A pencil case is really handy to put your stationery. You use them at work, school, uni, everywhere! But they are so expensive, so this article will teach you how to sew your own. All you need is the things below and a basic sewing skill!
1Cut the fabric about 18cm (the LENGTH of your pencil case) by about 15cm (half of the WIDTH of your pencil case).
2Fold the fabric in half lengthways, just enough to make a slight crease in the fabric. If you wish, you can measure half-way and draw a faint line.
3Unfold it.
4Now fold the two sides lengthways to the crease. As you might predict, the zipper is going to be sown in the middle between the two edges touching.
5Fold the edges slightly back, about 1 centimeter (0.4 in), to make room for the zipper.
6Sew the WIDTH using a basic running stitch.
7Align the zipper, FACE DOWN, in the middle where there is a small gap between the two folded edges.
8Sew it on with a running stitch.Keep the zipper slightly open, enough to place your finger through.
9Poke your finger in the zip and carefully zip it open.
10Turn out.
11You have your new pencil case! Decorate it with buttons or some cute embroidery. To seek more durability, find instructions how to sew a lining for your pencil case. This is entirely optional, but it keeps the shape of the pencil case while still giving protection to your stationery.
Community Q&A
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- Make sure your knots won't come undone.
- Try experimenting with stripes and dots! You can cross-stitch them or just sew it on the fabric first. *Remember the fabric is going to be turn inside out.
Things You'll Need
- Sewing Needle
- Thread
- Scissors
- Fabric (e.g. cotton)
- Lining material (optional)
- Buttons (optional, for decoration)
- Zipper - about 20 centimeter (7.9 in).
Made Recently
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subset: commoncrawl


text:
Back in '96 Drayton McLane and the Astros were recruiting community heavy hitters to support a referendum to build the downtown baseball stadium now known as Enron Field. The team's owner promised that minorities and women would receive 30 percent of the stadium revenues, including the food and drink concessions.
That pledge won McLane the allegiance of black ministers and civil rights leaders and a narrow victory in the referendum. It even helped get him over a bad public relations patch when a Hispanic television executive accused him of making racially tinged off-microphone remarks about Hispanic baseball fans.
Last week the Astros owner's promise came true. Legal papers were signed carving out a third of a 15-year stadium food service contract for minority investors, although many of the beneficiaries are better known for cooking political deals than hot dogs.
Of course the ubiquitous City Hall insider lawyer Zinetta Burney is in the mix, as is City Hall lobbyist and former HISD board member Paula Arnold and Metro board member Olga Moya, an environmental law professor. They are participants in a group called Women Stadium Investors. Former city councilwoman Gracie Saenz leads a group of Hispanic investors. Merida's operator Rafael Acosta, an electrical engineer who once sat on the Metro board and ran a losing race for Harris County judge, is teamed with banker Ben Ho as a general partner in Houston Limited Partnerships. Melanie Wong, the daughter-in-law of former city councilwoman Martha Wong, heads an Asian-American group. Then there's attorney Tony Chase, son of architect John Chase, a fixture in Mayor Lee Brown's inner circle. And then there's well, you get the picture.
As in previous affirmative action controversies at City Hall, the question arises as to who is really benefiting from the stadium food deal -- the "minority" community that is under-represented in local business ventures, or a select crew of political insiders taking advantage of their connections to win a place at the table?
In case you're worried about whether any of these folk can cook a lick, keep in mind that food service giant Aramark will sell the popcorn and peanuts, boil the wieners and tote the kegs at Enron Field. After the referendum barely passed and stadium construction began, the Astros negotiated a contract with Aramark that included strict investment guidelines.
"Since that goal was stated and out front, we felt it was necessary in the concession agreement," recalls Mike Puryear, senior vice president of operations for Enron Field. "When we sat down with the concessionaires, we said, 'Look, we've made this goal and commitment of a 30 percent minority community participation in this facility, and we feel like this is something you need to do.' "
For Aramark, it was no problem. The Urban League leader who helped prevail on McLane to make the original commitment was Darryl "Chicken Man" King, the food concessionaire who also happens to be a partner with Aramark in other ventures.
The next sticky question became how to apportion the food services at the stadium among Aramark and its new partners.
"Do you designate this stand or that one as a minority stand?" asks Puryear, whose rolling Southern accent transforms the word to "my-nority." "Then you get into the situation of 'Well, the minority stand is either right behind home plate or it's way up there in the upper deck. Now which stand do you want?' So we thought, look, that's not the way to do this."
Investor Arnold describes the dilemma more succinctly. "Location's everything. If you're behind home plate at field level, you're in great shape. If you're in right field and it's a slow day, you're screwed."
After mulling over the options, the Astros and Aramark "felt like the fair way to do this thing is, let's not give 'em a stand to operate, let's give 'em the whole business," Puryear says. "If they're going to participate, they're going to own 30 percent of the whole business."
It became a much simpler proposition. No getting the hands dirty running a food stand or the hassle of hiring staff for intermittent employment. Aramark would do the work, while the minority investors would feed money into the stadium machine, and hopefully take more money out in the future. Presumably the abstract "minority community" would eventually benefit if a few well-known members profited from the stadium sales.
Restaurateur Acosta says that the more he studied the proposal, the more he and his partners liked it. "If we had the concession there, we'd have our restaurant's name there," reasons Acosta. "But then you have to find people to run it and operate it, and try to make a profit. I feel, having a business background, that this is a much better deal for us.It takes a lot of the risk out, I believe."
Aramark set a minimum buy-in of $100,000 for investment candidates. Since Aramark paid the Astros nearly $20 million for its portion of the build-out at the stadium, the minority investors as a group were expected to put up more than $5 million in total capital. Of course, once an investor was included in a lucrative long-term stadium contract, financing for his or her share of the deal would be much easier to secure. One source says Aramark was also willing to make loans to favored investors.
Having figured out the how, Aramark hired the minority law firm of Wickliff & Hall to take care of the who. Firm attorney Suewan Johnson supervised the selection process, which involved requests for proposals from minority firms and individuals. The process began in earnest a year ago, when officials of the Astros and Aramark held a spring training session to acquaint minority hopefuls with the rules of the game. The first was that Aramark would handle all the food and beverage operations. This caused some initial grumbling from participants who owned restaurants, but it didn't take long for the advantages of the proposal to become apparent.
"One of the special things about stadiums is you can only have one liquor license for the venue," says Arnold. "The [concession] money in stadiums is in the alcohol. That's a problem in terms of cutting it up into little pieces." Since Aramark would hold the license, the investment arrangement allowed the minority investors to share in that stream of liquid profits.
Aramark then selected the final group of investors. An Aramark representative did not return an Insider call seeking a complete list of the participants. Puryear says he doesn't know the full roster, but that the investors -- as well as a complete sampling of stadium chow and drinks -- would be accessible to the media this week at an open house at Enron Field.
For Arnold, induction into the Enron Hall of Minority Investors worked this way: To become an investor, at least one member of each group had to have attended the initial meeting at the Astrodome. Arnold had already recruited four other women friends, including Moya and Cheryl Creuzot, the wife of Frenchy's operator Percy Creuzot. Since Burney had been at the initial meeting, her inclusion in Women Stadium Investors made the group eligible for the deal. Aramark further bundled Tony Chase and the black-owned LaTrelles food service together with Women Stadium Investors for a 7 percent piece of the contract.
Arnold says no one is expecting to get rich quick, but Enron Field is a sound and prestigious investment.
"I wanted to participate in it because it's the stadium, and it's a big deal in town. We all thought it would be a fun investment. Not something we're going to make boatloads of money [on], but not a bad investment with a reasonable return."
Arnold takes issue with the notion that she and others used their political connections to get in on the contract.
"It was an open RFP," says the lobbyist, referring to requests for proposals. "It wasn't an inside deal. The meeting was open, and they put out notices." She says Aramark made the decision and adds, "I doubt the mayor has any idea who is participating."
Acosta agrees that the process was open and anyone who wanted to get in had an opportunity. "There were a lot of people at the first meeting," he says. "Some people decided this was a good deal, and some people may have decided this wasn't for them. At no point did they say, 'You have the second option, and the first option is for people connected with the city.' I didn't feel that was the case."
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Puryear says his boss, Drayton McLane, made good on his campaign promise to give minorities their fair share.
"From my understanding and from the representation that I have seen," Puryear says, "it is a group that is representative of the minority community here in Houston."
And perhaps more than representative of the members who can deliver the votes.
Aramark is for hot dogs, the Insider's for hot news tips. Call him at (713)280-2483, fax him at (713)280-2496, or e-mail him at firstname.lastname@example.com.


text: WTA Championships 2011 - Red Group preview Live Tennis Staff in Tennis News 24 Oct 2011 0 share Share Tweet Email Share RedditWozniacki is yet to win this tournament. (credit: Wikimedia) As the draw for the round robin stage of the WTA Championships was announced on Sunday, we take a closer look at the red groupYou can watch and bet on the action from the WTA Championships at bet365Caroline Wozniacki was the runner-up in last year's WTA Championships, where she fell in the final against Kim Clijsters. The Dane returns here as the top seed, and she'll be looking to finally get her hands on the title. She's got a lot of work to do though, as her group includes Petra Kvitova, Vera Zvonareva and Agnieszka Radwanska.Wimbledon champion Kvitova is a big threat here, especially after her recent title success in Linz. She's won five titles this year, and her displays in the tail end of the season have been impressive. There's a reasonable chance that the Czech will progress from the group.World No. 6 Zvonareva will also be worth keeping an eye on. She's been consistent throughout the season, and having reached the final of this competition in 2008, will be eager to go one better and top the field. This will be her fourth successive appearance at this tournament.Radwanska, the eighth seed, should also be competitive. She takes a 11-1 post U.S Open match record into this week, and recent title successes in Tokyo and Beijing put her in a good position to challenge.You can watch and bet on the action from the WTA Championships at bet365


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Legal Question in Traffic Law in Florida
I am involved in a car accident and I received the ticket but now checking on my phone instead of taking picture at all time, it looks it switched to video and I got the other person involved in the accident stating something totally different to what she told the police when he arrived. my question is:
Can I use this in court or I made a mistake without knowing and I can get sue over for that?
Asked on 7/01/13, 1:59 pm
1 Answer from Attorneys
Craig Epifanio Craig Epifanio, P.A.
It's difficult to say if what you did was illegal. There was no expectation of privacy on the open street, but it could be that some conversations may or may not be admitted. You should get an attorney to represent you on the ticket and they can decide if it will be useful for you.
Answered on 7/01/13, 2:38 pm
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JONAH Arabic Yunus يونس
Mentioned in the Qur'an as a prophet, and as Sahibu 'l-Hut and Zu 'n-Nun, "he of the Fish."
Surah xxxvii. 139-148: "Jonas, too, was one of the Apostles (mursalin), when he fled unto the laden ship, and lots were case, and he as doomed, and the fish swallowed him, for he was blameworthy. But had he not been of those who praise Us, in its belly had he surely remained, till the day of resurrection. And we cast him on the bare shore – and he was sick; – and we caused a gourd-plant to grow up over him, and we sent him to a hundred thousand persons, or even more, and because they believed, we continued their enjoyments for a season."
Surah lxviii. 49050: "Patiently then await the judgement of thy Lord, and be not like him who was in the fish (Sahibu 'l-Hut), when in deep distress he cried to God. Had not favor from his Lord reached him, cast forth would he have been on the naked shore, overwhelmed with shame: but his Lord chose him and made him of the just."
Surah x. 98 (called the Suratu Yunus), "Verily they against whom the decree of thy Lord is pronounced, shall not believe, even though every kind of sign come unto them till they behold the dolorous torment! Were it otherwise, any city, had it believed, might have found its safety in it faith. But it was so, only with the people of Jonas. When they believed, we delivered them from the penalty of shame in this world, and provided for them for a time. But if thy Lord had pleased, verily all who are in the earth would have believed together. What! Wilt thou compel men to become believers?"
Surah vi 86: "We guided…. Ishmael and Elisha, and Jonah, and Lot."
Surah xxi. 87: "And Zu 'n-Nun (he of the fish), when he went on his way in anger, and thought that we had no power over him. But in the darkness he cried, "There is no God but Thou: Glory be unto Thee! Verily, I have been one of the evil doers'; so we heard him and rescued him from misery; for thus rescue we the faithful."
[Sale, i his Note on the Qur'an, quoting from al-Jalalan and al-Baizawi, say: "When Jonah first began to exhort the people to repentance, instead of hearkening to him, they used him very ill, so that he was obliged to leave the city, threatening them at his departure that they should be destroyed within three days, or , as others say, within forty. But when the time drew near, and they saw the heavens overcast with a black cloud which shot forth fire and filled the air with smoke and hung directly over the city, they were in a terrible consternation, and getting into the field, with their families and cattle, they put on sackcloth and humbled themselves before God, calling aloud for pardon and sincerely repenting of their past wickedness. Whereupon God was pleased to forgive them, and they storm blew over. It is said that the fish, after it had swallowed Jonah, swam after the ship with its head above water, that the prophet might breathe, who continued to praise God till the fish came to land and vomited him out. Some imagine Jonah's plant to have been a fig; and others, the moz (or banana), which bears very large leaves and excellent fruit, and that this plant withered the next morning, and that Jonah being much concerned at it God made a remonstrance to him in behalf of the Ninevites, agreeably to what is recorded in Scripture."]
Based on Hughes, Dictionary of Islam


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Purple Onion Designs recently announced their new creative team members. They are joining the existing members who are staying. The new members are: Aimee Westcott, Anna Bjorklund (Sweden), Christine Penaflor, Courtney Kelley, Hilde Janbroers (Netherlands), Jennifer Holmes, Julie Dudley (Australia), Laura Craigie (Canada), Meg Shumaker, Nathalie Mejdoub (France), Sharon Ong (Singapore), Susan Lui (Singapore) and Waleska Neris.
The newest Bella Artistas for Bella Blvd are: Jessica Jo Salber, Erin Wells, Dana DiGennaro, Becky Heisler, Paula Gilarde, and Hilde Janbroers.
I think we missed this one a few weeks back… Bind-it-All's new Design Team is: Annette West, Claire Labigne, Emeline Seet, Jennifer Priest,
Gretchen Schmidt is the October Guest Designer for Paper Posies. You can see some of her work here.
Upsy Daisy Designs new Design Team announced this month is Michele Beck and Kim Sonksen. Guest Designers are Christa Pausternbaugh, Amanda Muirhead, Wendy Polzin, Virginia Wong, and Mette Kallander.
Angela Ploegman was recently added to the Reminisce 2009 Design Team. You can read the announcement here.


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The News Line
: Feature
Monday, 2 November 2009
One hundred BECTU and NUJ members rallied outside Bush House for the reinstatement of the sacked workers
ONE HUNDRED BECTU and NUJ members demonstrated outside Bush House in Aldwych, Central London last Friday, in support of ten workers sacked from the BBC World Service canteen.
BECTU and the NUJ issued a joint statement, saying: The BBC has failed to consult meaningfully with the recognised trade unions over the reduction to the catering provision at Bush House, and despite the serious concerns the joint unions have raised, management has gone ahead and imposed cuts in catering provision.
The sacking of Aramark workers has come about as a result of cuts in catering provision.
It is morally repugnant for low paid catering workers to be treated in such an appalling fashion.
The statement went on: The BBC has imposed a reduction in the provision of catering services and Aramark have sacked staff as a result of this, including two elected BECTU representatives.
The unions organised Fridays mass protest and a boycott of the canteen for the day.
Sacked worker Joyce Danso told News Line: They are using refurbishment as an excuse to make us redundant.
Ive worked here for nine years as a general assistant and over these nine years Ive worked for four different contractors. Ive been moved from contractor to contractor. The last one was Compass and they moved us to Aramark and now this has happened its terrible.
We are all very angry and determined to beat them. We are not going to just let them get away with it.
Fellow sacked worker and Bectu member Ernest Omane said: I joined the BBC at the same time as Joyce. Ive always worked hard and done my job very well.
We are proud so many of our BBC colleagues and fellow Bectu members came out here to support us today, and the NUJ.
Now we need more action. The unions shouldnt let it drop because if they get away with it to us they will do it to everyone.
On 23rd October, Aramark just said get out! After nine years! Not even a card, or a handshake, or a goodbye.
Ash Akram said: Ive been with the company five years two of them as head chef.
When I first came they set a target to bring up the standard of food, which I did.
I received two awards one bronze, one silver one for great customer service, the other for high quality food.
Its absolutely disgusting the way theyve gone about things.
There are ten of us. We are very tight-knit and determined to win justice.
They are heartless and ruthless and we are going to beat them. Of course, the BBC are partly to blame as well, they are the ones who brought these private contractors in and they are the ones who are trying to make them cut their costs.
Tanya Pearson said: Ive worked here for six years and theyve made sure that my family and myself are not going to have a pleasant Christmas.
Its heartless of them and spiteful. They didnt even have the decency to offer me alternative employment.
Aramark is a massive company worldwide and so I find it very hard to believe they couldnt find me a suitable alternative.
All Id like to say to Aramark is thanks for being so kind and caring to my children not!
Nuala OSullivan, a writer for BBC Learning was one of those who came out to support the sacked workers. She told News Line: The provision in the canteen has got worse. There are no longer hot meals through the night.
Ten workers were brought into a room and told pack your bags. Its a disgrace and it represents a threat to all BBC workers.
All these workers must be reinstated.
BECTU General Secretary Tony Lennon told the rally: These are not highly paid workers at all.
Aramark pay wages at or only just above the minimum wage.
This is in marked contrast to the fantastic wages they pay themselves.
We condemn the company for the changes in the canteen opening hours and the deterioration in the range of food.
We are demanding the canteen services are restored and the people who Aramark have sacked, who have been working at the BBC for years, are reinstated.
Mark Workman of the National Union of Journalists, told the rally: You have full support from the journalists in Bush House.
Aramark may have pulled the trigger, but Mark Thompson (BBC Chief Executive), on £800,000 a year, gave the orders.
This is a spiteful, ill-thought-out move and the NUJ at Bush House will stand alongside you until justice is done.
Pat Styles, Bectu National Officer, said: Ten of our members have been dismissed allegedly made redundant.
We are going through appeals, but the company is making it as hard as they can. They are actually banning those they have sacked from coming in and bringing in their appeal forms.
We are in dispute with the BBC and its a wider issue. Aramark deliver catering services across the BBC and this could be the first of many cuts.
We are determined to get justice for our members.
He added: The BBC has failed to consult meaningfully with us about the proposed changes to catering provision at Bush House, and despite the serious concerns we have raised, management has imposed a cut in the service.
On the same day as these reductions were imposed we also discovered that Aramark had dismissed several of our members, including some of our elected representatives.
BECTU officer Helen Ryan, said: What has happened to our members is absolutely disgusting. Aramark has not given any consideration to redeployment opportunities, or other suitable alternatives to dismissal, and our members were called in one by one last week and told that when the Bush House restaurant reopened after its refurbishment they would not be needed. This is no way to treat anybody.
We are seeking meaningful negotiation and consultation with the BBC regarding the provision of catering services to our members working at Bush House.
We are calling upon Aramark to reinstate the sacked workers whilst proper negotiations and meaningful consultation takes place.
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Louise Gray
London Telegraph
April 30, 2012
Usually at night the air closer to the ground becomes colder when the sun goes down and the earth cools.
But on huge wind farms the motion of the turbines mixes the air higher in the atmosphere that is warmer, pushing up the overall temperature.
Satellite data over a large area in Texas, that is now covered by four of the world's largest wind farms, found that over a decade the local temperature went up by almost 1C as more turbines are built.
This could have long term effects on wildlife living in the immediate areas of larger wind farms.
It could also affect regional weather patterns as warmer areas affect the formation of cloud and even wind speeds.
This article was posted: Monday, April 30, 2012 at 8:42 am


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October 31, 2011
On Sunday night, the Phoenix Coyotes held their annual Halloween Party, and winger/Internet godsend Paul Bissonnette(notes) posted a few photos on his popular Twitter feed — including one of BizNasty as WWF legend "Hacksaw" Jim Duggan, complete with 2x4 but without the old-man flab.
Oh, and also this one above of winger Raffi Torres(notes) covered in brown makeup as Jay-Z.
Wait … what?!
Yes indeed, Coyotes forward Raffi Torres attended this holiday soirée as Jiggaman, while his wife dressed up as Beyonce (complete with baby bump).
To the surprise of absolutely no one in 2011, Torres was immediately criticized and demonized for using "blackface" for comedic effect.
Bissonnette, catching the whiff of outrage, later tweeted:
As far as everyone trying to call "Racism" because Raffi dressed up like Jay-Z can simmer down. He's a huge Jay-Z fan.
(Incidentally, these guys were also huge fans of PK Subban.)
So Raffi Torres has 99 problems and having half the hockey world calling him a racist is one. Thomas Drance of Canucks Army writes:
Seriously people, don't do it, don't wear black-face on Halloween, or ever. It's stupid, it's ignorant, and it just doesn't fly. [...]
Even if Raffi's halloween costume bears little resemblance to the blackface of minstrel shows, the subject is too loaded to be a source of humour. It's off limits.
But before attacking Torres for this costume, understand a few things about him and about hockey players dressing as black men on Halloween. Because he isn't the first.
First off, despite looking so white as to be translucent during his career, Torres is actually the NHL's first player of Mexican and Peruvian descent.
He dealt with racial insensitivity while playing youth hockey in the Greater Toronto Area — his mother once being told that Raffi "should be selling tacos" and his father tackling another hockey parent because of taunts, according to the Columbus Dispatch.
This isn't meant to exonerate Torres from any racial insensitivity, but rather lend some context.
More context: All of this has happened before, and will happen again. Just ask Adam Burish(notes) of the Dallas Stars and Patrick Kane(notes) of the Chicago Blackhawks.
In 2009, they attended a Halloween party dressed as Dennis Rodman and Scottie Pippen of the Chicago Bulls, with darkened skin for effect.
An image from the party stirred considerable debate and a backlash, but with some media outlets also claiming the criticism was overblown, such as from Big League Screw:
The offensive nature of "blackface" is rooted in its representation of a racist archetype. Clearly, the Blackhawks players were dressed and made up as real people rather than a stereotype manifested through exaggerated appearance. Other than the color of their skin, there's nothing stereotypical or embellished about their appearance as black men. It could be argued that their skin tone is as relevant as the jersey or fake tattoos.
Neither Burish nor Kane offered a public apology for the costumes. They shouldn't have, and neither should Torres.
Granted, there is a movement afoot to demonize costumes that deal with stereotypes. The Ohio University Group has an ad campaign this year dealing with costumes that focus on different cultures, like a Native American or an African-American rapper.
But again: It's a costume on Halloween. It's a character. It's Robert Downey Jr. in "Tropic Thunder" or Eddie Murphy going undercover as a white guy on SNL. It doesn't matter if Torres was doing this for a laugh or as a tribute -- there's nothing patently offensive about this image. (In fact, let's be honest: This was probably her idea. Couples costumes usually are.) The only racial insensitivity here is on the part of the critics.
But what do I know? I'm a pudgy white guy from the Jersey suburbs. Who, incidentally, is dressing like a Japanese ninja for Halloween. No photos, please.
Gary Bettman's unlikely musical tastes
Posted Jun 21 2012
Yakupov says he's ready for NHL
Posted Jun 25 2012
Canada's Stanley Cup curse explained
Posted Jun 21 2012
Edited By Doug Farrar
Edited By 'Duk
Edited By Kelly Dwyer
Edited By Greg Wyshynski
Edited By Matt Hinton
Edited By Jeff Eisenberg
Edited By Jay Busbee
Edited By Jay Busbee
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Edited By Chris Chase
Edited By Chris Chase
Edited By Brooks Peck
Edited By Andy Behrens
Edited By Cameron Smith
Edited By Mark J. Miller


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Haute Society: 2011 Bal des Debutantes at Hotel Crillon
The 2011 Bal des Debutantes (also known as Le Bal) took place Thanksgiving Weekend on the magical Place de la Concorde. I happened to be in Paris the very next weekend for another bal which took place at the Palace … Continue reading
Posted in fashion, Haute Society Tagged Bal des debutantes, Bruce Willis, Charlotte de Bourbon-Parme, Crillon Bal, demi moore, Eliza Fraser, fashion couture, Flora Collins, Hikari Mori, Hotel Crillon, Lauren Bush, Leana Mallya, Marie-Sarah Carcassonne, Oriane Piccard, Paris, Place de la Concorde, Sarah Margaret Qualley, Tallulah Willis, Vivian Chou Leave a comment


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I know, I know…you are thinking, "Jill, why didn't you post this on New Year's Eve?" Well, I didn't find it until now lol! Plus, there will be plenty of times that you will need to refer to these hangover cures. I know I am going to study this list very carefully before my bachelorette party!!!!
I found the following hangover cures on yahoo.com:
1. Drink Water
An evil hangover is all about dehydration. So gulp plenty of water post-party and the morning-after to rehydrate. Better yet, prevent a hangover altogether by drinking a water for every cocktail you sip! – I 100% agree with this. Drinking water WHILE drinking helps soooo much with the hangover!!!!
2. Chow Down
Pizza, egg sandwiches-hangovers often lead to fast food feasts. But docs at the Mayo Clinic say bland snacks like toast, and crackers are best for boosting blood sugar and settling an upset stomach. – Guilty as charged when it comes to eating fast food after a night of drinking. Then one fast food meal leads to fast food all day and night. Maybe I should try crackers next time!
3. Globe Artichoke
Holistic health says that these delicious, yet tough-to-crack, veggies contain substances that can reduce bloating and nausea, two common symptoms of hangovers. According to Sarah Brewer, MD, they can also help protect liver cells from booze. Does spinach artichoke dip count? – I love artichokes!!!!!!!! I don't see myself taking the time to prepare one though. Can I eat them out of the can?
4. Coconut Water
Trendy coconut water is a sort of natural Gatorade. The Food and Agriculture Organization (FAO) says coconut water has the same five electrolytes found in our blood, which will help you rehydrate post-partying. – I have actually heard this helps a hangover, but have never tried it. I will keep a couple of bottles on hand in preparation.
5. Amazing Eggs
James Bond's preferred hangover method was the prairie oyster-a raw egg, some Worcestershire sauce, hot sauce, salt, and pepper in a glass. But since raw eggs are scary, reach for cooked ones-they're packed with cysteine, an amino acid vital to detoxing, even if scientists remain dubious. – I can never eat eggs after drinking. Something about them makes me want to vomit. I love eggs, but not after drinking so this cure will not work for me.
6. Vitamins
They're not a cure-all, but a University of California study found that B-Complex vitamins can help hangovers by restoring energy to your aching body. – Makes sense.
7. Lemon Pits
Literally-lemon pits. Some revelers in Puerto Rico swear by rubbing a slice of lemon (or lime) in your armpit before drinking, or afterwards to fight hangover dehydration. We doubt this really works, but, bonus: natural lemony deodorant? – Interesting!
8. Milk Thistle
Always consult a doc before taking any sort of supplement, but this liquid herbal extract is said to work as a "liver tonic." And we all know excessive drinking = bad for your liver. – Any time the word "doctor" is associated with hangover cures, I will probably pass.
9. Evening Primrose Oil
It sounds like a luxurious bath product, but this oil from the flowery primrose plant is an age-old alleged hangover cure, as it can help cut down on stomach discomfort and help along liver function. But take it with a grain of salt, as study results are mixed. – I'll pass.
10. Sweat
You're not actually sweating out that tequila when you hit the gym the morning after your holiday party. But exercise can help in the way of endorphins! – Who wants to work out after a night of drinking!!??!?! That sounds miserable. Another cure I will go ahead and pass on.
11. Sleep
Time heals all wounds, including hangovers. Docs at the Mayo Clinic say the best remedy is to go back to sleep and hope your hangover is gone by the time you wake up! – This is my favorite cure!!!!!!!!!!!!


text: > you can use 'explicit' soname: > glibversion guileversion gwrap-glib-1-soname > 1.2 1.4 1-glib1.2-guile1.4 > 1.2 1.6 1-glib1.2-guile1.6 > 2.0 1.4 1-glib2.0-guile1.4 > 2.0 1.6 1-glib2.0-guile1.6 > > I am not sure this is the right solution, but this scale much better than using > 1,2,3,4. and it will be easier to handle in the long run, and is > self-explanatory. Also the soname is not mixed with the name. > If you are using libtool and automake, it would be: LDFLAGS = ..... -release @OTHERLIB_NAMES@ and checking other sonames in configure time: OTHERLIB_NAMES=whatever6-whateverelse3-whateverelse2 However, I don't know of a way to reliably check sonames in configure scripts... but reading APT source, for rc_LIBSTDCPP_VER, it seems to be possible. regards, junichi


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Court: Irish Nobel Laureate to Be Deported From Israel
Nobel Peace Prize laureate Mairead Corrigan-Maguire, who was deported from Israel after joining a Gaza-bound aid ship, is currently in a detention facility at the airport pending an appeal to the Supreme Court.
The Petah Tikva District Court rejected Friday an appeal against the deportation of Irish Nobel Peace Prize laureate Mairead Corrigan-Maguire, who has been denied entry to Israel.
The Nobel laureate's deportation, however, has been suspended for 48 hours in order to allow Corrigan-Maguire to appeal to the Supreme Court.
Corrigan-Maguire has been in a detention facility at Ben-Gurion International Airport since she was stopped by police for contravening a prohibition against entering Israel, imposed after she took part in a mission aimed at violating Israel's naval blockade on the Gaza Strip, aboard the Rachel Corrie ship, in early June.
The MV Rachel Corrie was intercepted in June after the Gaza-bound aid ship refused to adhere to Israel's requests to dock in the country and transfer its cargo to Gaza after inspection. The ship was then transported to the Ashdod port, and its passengers were deported from the country.
Before she was deported, Corrigan-Maguire signed a document stating that she was prohibited from entering Israel for the next 10 years. Corrigan-Maguire, however, says she was misled and had not agreed to such a condition.
High Court Justice Esther Hayut ordered the Petah Tikva court to hear Corrigan-Maguire's case after hearing a petition submitted on behalf of the Irish peace activist on Wednesday at 1 A.M. by Adalah, the Legal Center for Arab Minority Rights in Israel.
Adalah asked Justice Hayut to issue a temporary injunction against Corrigan-Maguire's deportation. In addition to instructing the Petah Tikva District Court to hear the case, Hayut also ordered that Corrigan-Maguire's belongings be returned to her.
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