text:
Senior Software Engineer Jobs in Brighton, Massachusetts - Page 8
1000+ Brighton, MA Senior Software Engineer jobs found on Monster.Jobs 141 to 160 of 1034
Location: Cambridge, MA, US Posted Date: 2014-06-02 00:00:00.0 Category: Engineering ID: 11731 Overview: About the Team The Enterprise Cloud space is thriving and Akamai is growing with it! We're looking for top-notch technical staff to create core technology to deliver a secure, accelerated experience to enterprise customers. Our development environment is fast paced and ambitious. This s...
Location: Cambridge, MA, US Posted Date: 2014-10-17 00:00:00.0 Category: Engineering ID: 12787 Overview: About the Job Akamai's is expanding our investment in OpenSSL. Akamai is a leader in security and this software is key to our business and to the Internet. Our security engineering team is hiring talented engineers with strong applied security backgrounds and expertise developing secur...
Location: Cambridge, MA, US Posted Date: 2014-07-22 00:00:00.0 Category: Engineering ID: 11978 Overview: About the Job We need an experienced engineers to create designs, implement systems and build products that enable innovation for our customers with focus on performance and scale. We currently receive about 2 trillion daily requests and recently surpassed handling over 20 terabits of data...
Location: Cambridge, MA, US Posted Date: 2014-08-27 00:00:00.0 Category: Engineering ID: 12414 Overview: About the Job As a security focused Senior System Software Engineer for Cloud Optimization, you will work in an Agile/Scrum environment to develop Akamai technology to accelerate Enterprise environments. You will utilize your software architecture and development skills, together with your ...
Location: Cambridge, MA, US Posted Date: 2014-10-21 00:00:00.0 Category: Software Engineer ID: 9203 Overview: About the Job Akamai's System Communications team is looking for a talented software engineer to join our Distributed Reporting team. This engineer will be involved with the design, implementation and maintenance of a global distributed system for retrieving and aggregating perfor...
Location: Cambridge, MA, US Posted Date: 2014-01-24 00:00:00.0 Category: Engineering ID: 9710 Overview: About the Job Akamai's System Communications team is looking for a talented Lead Senior Software Engineer to join our Platform Engineering team. You will lead a team responsible for developing and managing a critical system for managing virtualized instances of Akamai's distributed plat...
Location: Cambridge, MA, US Posted Date: 2014-10-17 00:00:00.0 Category: Engineering ID: 12802 Overview: About the Job Akamai's System Communications team is looking for a talented software engineer to join our Security Engineering team. This engineer will be responsible for developing features within Akamai's core internet, writing software runs on one of the largest distributed sys...
Location: Cambridge, MA, US Posted Date: 2014-08-01 00:00:00.0 Category: Engineering ID: 12041 Overview: About the Job The Luna Engineering group is growing in Cambridge. Akamai is looking for a strong Senior Systems Engineer to revolutionize the customer experience for Akamai's provisioning products. About the Team Our software underpins Akamai's exceptional level of customer service a...
Location: Cambridge, MA, US Posted Date: 2014-10-08 00:00:00.0 Category: Engineering ID: 12731 Overview: About the Job We are seeking a passionate, product-focused developer who thrives on delivering exceptional results and delighting customers. The person in this role will be developing Web Applications and Services for Akamai's core acelleration products in the Luna Control Center. Luna prov...
Location: Cambridge, MA, US Posted Date: 2014-10-23 00:00:00.0 Category: Software Engineer ID: 11551 Overview: About the Job Akamai is looking for a talented and accomplished software engineer to join a dynamic team designing a brand new way to deliver Internet content to users. This is an opportunity to join a groundbreaking project early and to influence, design, implement, and own an innova...
sanofi-aventis U.S. LLC. Cambridge, MA, 02138
Sanofi, an integrated global healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients' needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi US At Sanofi US, we are committed to the growth...
Amazon.com, Inc. Cambridge, MA, 02138
Audible, Inc Audible.com (a wholly owned subsidiary of Amazon.com ) is the Internet's leading provider of spoken audio programming including books of any genre, magazines, radio shows, daily newspapers, and more. Audible apps for your tablet or smartphone make it easy to listen wherever you are. Catch a caper while commuting in your car, add a little romance to a run, or maybe savor a mystery whil...
Overview: About the Job Akamai's Lead to Cash team is seeking a Senior Engineer to be responsible to design, implement, enhance, and maintain the enterprise web content management system, SDL Tridion. To succeed in this role, the versatile candidate must possess strong analysis, communication, development, and application support skills. This individual must be able to work both collaboratively ...
Overview: About the Job An Akamai product architect designs new customer-oriented products and features and is responsible for leading the end-to-end design of the product. The position requires a high degree of creativity and the ability to work "outside the box". This is not a high level architecture only position. A significant portion of a candidate's success will be measured by her/his abi...
Overview: About the Job Akamai's Lead to Cash team is seeking a hands-on Lead Engineer to be responsible to design, implement, enhance, and maintain the enterprise web content management system, SDL Tridion. To succeed in this role, the versatile candidate must possess strong analysis, project management, communication, architecture, development, and application support skills. This leader must ...
This company is one of the leading online marketplaces connecting Buyers who want one-of-a-kind creations with professional and passionate Makers of those goods. Building a growing two-sided marketplace platform that lets people buy anything they can imagine. In the U.S. alone, consumers spend >$600 billion per year on Furniture ($200B), Jewelry ($158B) and Apparel ($288B). An increasing portion ...
Senior or Principal to Lead Full Stack Software Engineer Our startup clients seek multiple software engineers from Senior or Principal to Lead Full Stack Software Engineer. Their technology stack makes extensive use of Ruby, Redis, Cassandra, PostgreSQL, Amazon EC2, and S3. Responsibilities: Leverage your professional experience delivering production Saas or PaaS software, use significant exper...
Overview: About the Job Akamai is looking for a Senior Software Development Engineer in Test to help with the a ground up rewrite of the Luna Control Center. This role will be working on the underlining Systems that Luna runs on and will be key participant in bringing Docker into Akamai's Infrastructure. About the Team Luna is Akamai's face to our users on the web. It provides a full range of ...
Overview: About the Job We are seeking an experienced, talented and highly motivated Linux kernel software engineer to join our expanding team. You will be responsible for the Linux kernel, the foundation of the Akamai software stack. Our kernel engineers develop and enhance the Linux kernel components that are critical to the Akamai business. You will work on our most challenging problems, diag...
Rapid7 Cambridge, MA, 02138
Company Overview: Rapid7's IT security solutions deliver visibility and insight that help you make informed decisions, create credible action plans, and monitor progress. They simplify compliance and risk management by uniquely combining contextual threat analysis with fast, comprehensive data collection across your users, assets, services and networks, whether on premise, mobile or cloud-based. ...
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Sr. Software Engineer
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subset: commoncrawl


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Antiretoviral therapy and the lipodystrophy syndrome, part 2: concepts in aetiopathogenesis.
ABSTRACT Clinical research has indicated that the use of nucleoside reverse transcriptase inhibitor (NRTI) and HIV protease inhibitor (PI) therapy is associated with a risk of long-term toxicity syndromes, and that the aetiopathogenesis of these adverse effects is independent of the antiretroviral effects of these drugs. In relation to the lipodystrophy syndrome, it appears that the most powerful determinant of subcutaneous fat wasting is an interaction between these two drug classes. In this review, possible mechanisms underlying the contributions of both PI and NRTI drugs are reviewed, with an emphasis on their effects on adipose tissue. On this basis, an 'adipocentric', or minimal model of the syndrome is developed, in which divergent effects at the adipocyte of NRTIs (mitochondrial toxicity) and PIs (insulin resistance and impaired adipocyte maturation) interact to produce a phenotype that is consistent with clinical observations.
Article: Is chromium an important element in HIV-positive patients with metabolic abnormalities? An hypothesis generating pilot study.[Show abstract] [Hide abstract]
ABSTRACT: Chromium plays a role in insulin sensitivity. To compare chromium measurements in HIV-positive patients with or without (N) antiretroviral therapy (ART) to that of healthy controls (HC) and, to determine if there is any association between chromium levels and abnormalities in body composition, glucose and lipid metabolism. A cross-sectional study in 91 HIV patients (75 HIV-ART, 16 HIV-N) and 13 HC. Chromium was assessed in the diet, plasma, toenails, and urine. Fasting blood glycemia and lipids, lipodystrophy score and body fat were also determined. Dietary intake of chromium was similar in the 3 groups. Plasma and toenail Cr were lower in HIV compared to HC, but urinary chromium was similar. However, when the HIV-positive patients on ART were compared to those who were naïve to therapies, urinary excretion of chromium was higher in HIV-ART. In addition, urinary excretion of chromium significantly and positively correlated with lipodystrophy score and negatively with various parameters of metabolic syndrome. Despite a similar dietary intake, chromium levels were lower in HIV-positive patients and urinary chromium excretion correlated with some metabolic parameters. Low chromium levels may be due to increased chromium losses. These results support further studies on chromium in HIV patients.Journal of the American College of Nutrition 03/2006; 25(1):56-63. · 1.74 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Pharmacogenomics classically focuses on host nuclear genetic polymorphisms that can be used to predict adverse drug reactions (ADRs). Because ADRs are defined as any noxious, unintended, and undesired drug effects, loss of efficacy due to the development of antiretroviral drug resistance and both acute and cumulative adverse effects of antiretroviral therapy can be considered ADRs. In order to address these types of antiretroviral-associated ADRs, pharmacogenomic testing methods have expanded to include molecular assays that characterize extranuclear genetic material (e.g. HIV and mitochondrial genomes), as well as the host nuclear genetic material. Recent molecular advances permit high resolution resistance testing that detects loss of therapeutic efficacy through the use of phenotypic, genotypic and/or virtual phenotypic resistance testing. These assays use complex technical and interpretative methods to improve the therapeutic efficacy of antiretroviral therapy. The resistance assays demonstrate the utility of pharmacogenomic testing for patients undergoing lifelong and complex antiretroviral therapies. Future applications of antiretroviral-directed pharmacogenomic tests range from quantitative detection of mitochondrial depletion as an early surrogate marker for drug toxicity, to qualitative analysis of host immune haplotypes, and metabolic/transporter genetic polymorphisms for predicting disease progression. In summary, pharmacogenomic testing for HIV-positive patients provides proof of principle that these tests can be used clinically to improve outcomes for patients undergoing complex and sustained drug regimens.American Journal of PharmacoGenomics 02/2004; 4(3):141-50.
- [Show abstract] [Hide abstract]
ABSTRACT: HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.Drugs 02/2003; 63(23):2555-74. · 4.13 Impact Factor
Page 1
Clinical research has indicated that the use of nucleoside
reverse transcriptase inhibitor (NRTI) and HIV protease
inhibitor (PI) therapy is associated with a risk of long-
term toxicity syndromes, and that the aetiopathogenesis
of these adverse effects is independent of the antiretro-
viral effects of these drugs. In relation to the
lipodystrophy syndrome, it appears that the most
powerful determinant of subcutaneous fat wasting is an
interaction between these two drug classes. In this
review, possible mechanisms underlying the contribu-
tions of both PI and NRTI drugs are reviewed, with an
emphasis on their effects on adipose tissue. On this basis,
an 'adipocentric', or minimal model of the syndrome is
developed, in which divergent effects at the adipocyte of
NRTIs (mitochondrial toxicity) and PIs (insulin resistance
and impaired adipocyte maturation) interact to produce a
phenotype that is consistent with clinical observations.
Antiretoviral therapy and the lipodystrophy
syndrome, part 2: concepts in aetiopathogenesis
David Nolan, Mina John and Simon Mallal*
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia
*Corresponding author: Tel: +61 89 224 2899; Fax: +61 89 224 2920; E-mail: firstname.lastname@example.com
Antiviral Therapy 6: 145-160
Clinical studies, whether based on observational
cohorts or clinical trials, have contributed significantly
to an increased understanding of the lipodystrophy
syndrome that accompanies long-term use of antiretro-
viral therapy [1]. Taken together, they provide a
conceptual framework that can inform basic science
research, with the ultimate aim of gaining an under-
standing of the underlying aetiopathogenesis of the
syndrome at the molecular level. The elucidation of
these mechanisms should then be able to guide the
selection of antiretroviral therapy combinations less
likely to induce long-term complications, as well as
provide a rational basis for the clinical management of
individuals with established lipodystrophy.
An analysis of the available clinical data was the
subject of a previous review [1], and will be briefly reit-
erated. This review also addressed methodological
issues relating to the clinical evaluation and definition
of the lipodystrophy syndrome. Of particular impor-
tance is the recognition that component clinical
features of the syndrome (body composition changes,
such as subcutaneous fat wasting and/or visceral or
localized fat accumulation; and metabolic abnormali-
ties such as insulin resistance and dyslipidaemia) need
to be analysed separately, so that their relation to each
other, as well as to interventions, such as introduction
or cessation of antiretroviral drugs, can be objectively
Initial aetiopathogenic models of the lipodystrophy
syndrome focused primarily on the role of HIV
protease inhibitors (PIs), as the introduction of this
class of drug into clinical practice was temporally asso-
ciated with the first descriptions of the syndrome. It
has since become apparent that subcutaneous fat
wasting, in particular, can also occur in patients
receiving only nucleoside reverse transcriptase
inhibitors (NRTIs) [2,3], and that NRTIs contribute to
lipodystrophic changes in body composition when
both drug classes are used in combination [4]. PI use
appears to be more strongly associated with the 'meta-
bolic' component of the syndrome, characterized by
increased levels of triglyceride, triglyceride-rich
lipoproteins and insulin resistance, based on the obser-
vation that these metabolic changes have been
observed after short-term exposure to PIs in healthy
volunteers [5,6], and following introduction of PI
therapy in HIV-infected patients in the absence of
changes in body composition [7,8]. NRTIs, on the
other hand, while contributing to the risk of devel-
oping peripheral fat wasting [2–4], appear to have
relatively less effect on lipid metabolism and insulin
sensitivity [1].
Assessing the effects of specific drugs within these
two drug classes, there is no current evidence that
choice of PI significantly affects the incidence or
severity of morphological [9] or metabolic [10] compo-
©2001 International Medical Press 1359-6535/01/$17.00 145
Page 2
nents of the lipodystrophy syndrome, with the notable
exception that ritonavir therapy is associated with
higher triglyceride levels [10,11]. Within the NRTI
class there is evidence from observational studies, as
well as randomized clinical trials, that stavudine
therapy is associated with an increased relative risk
(approximately twofold) of peripheral fat wasting
compared with zidovudine [2–4,9,12–14].
An important concept that has recently emerged is
that when NRTIs and PIs are combined in highly active
antiretroviral therapy (HAART) regimens, it is the
interaction of these drug classes that is the most
powerful predictor of lipodystrophic body composi-
tion changes, with a significant (>5-fold) increase in
relative risk compared with the use of one drug class.
This observation has now been made in clinical trials,
in which NRTI therapy is introduced to pre-existing
dual PI regimens [15–18] as well as in the more
familiar comparison of dual NRTI regimens versus PI-
containing HAART [4] (Figure 1). The magnitude of
this interaction effect in clinical studies is far greater
than observed differences in immunological or virolog-
ical response to dual therapy regimens (either PI- or
NRTI-based) [4,15–18] compared with combination
HAART, indicating that the interaction between these
drug classes is not mediated by a non-specific effect on
immune restoration. This is probably best exemplified
in the Prometheus study, in which the addition of
stavudine to stable long-term ritonavir/saquinavir
therapy had no significant effect on virological or
immunological response [16], while the relative risk of
developing clinically apparent changes in body compo-
sition increased ~fivefold [15]. This is also true for
differences within the NRTI class, where equivalent
anti-HIV efficacy but divergent effects on lipodys-
trophy have been shown in comparisons of zidovudine
and stavudine therapy [2–4,12].
In this review we propose to further examine the
effects of PI and NRTI therapy that may be relevant to
the aetiopathogenesis of the lipodystrophy syndrome,
and to explore how these effects may interact at the
molecular/cellular level to produce the lipodystrophy
phenotype. We propose a 'minimal model' of lipodys-
trophy pathogenesis that focuses on adipose-specific
effects, and accounts for the clinical observations, in
an attempt to provide a theoretical framework for
further research. Undoubtedly this model will require
modification in light of the results of future studies, as
knowledge of the underlying mechanisms is refined.
The contribution of NRTIs to lipodystrophy
The lipodystrophy phenotype that is observed in PI-
naive NRTI-treated individuals differs in some
respects to that seen in association with PI treatment.
Subcutaneous fat wasting appears to be a dominant
manifestation [19], and although mild increases in
visceral adiposity have been observed in clinical
studies [2,9], the magnitude of this effect is far less
than that observed in PI-treated patients [9,20], and
does not appear to be influenced by choice of NRTI
D Nolan et al.
©2001 International Medical Press
Probability of remaining free of
subcutaneous fat wasting / LD
Time from dual therapy to fat wasting / LD (days)
Dual NRTI therapy
Figure 1. Nucleoside reverse transcriptase inhibitors and protease inhibitors interact to cause fat wasting in highly active
antiretroviral therapy-associated lipodystrophy
Combining the results of the Prometheus study* and the Western Australian HIV Cohort Study† demonstrates the interactive effect on fat wasting of combining
nucleoside reverse transcriptase inhibitors and protease inhibitor therapy, compared with dual nucleoside reverse transcriptase inhibitors or dual protease inhibitor
regimens. NRTI, nucleoside reverse transcriptase inhibitor; RTV, ritonavir; SQV, saquinavir; d4T, stavudine; LD, lipodystrophy.
Page 3
In terms of the metabolic component of the
syndrome, studies by Saint-Marc [2] and Galli et al.
[21] have demonstrated mildly elevated levels of
triglycerides and decreased HDL cholesterol in stavu-
dine-treated patients. Risk of developing these
metabolic alterations was not found to be associated
with body composition changes [21], suggesting that
NRTIs may have an independent effect on some
aspects of lipid metabolism. However, the addition of
stavudine to dual PI regimens produced no incremental
rise in triglyceride or cholesterol levels, suggesting that
these lipid changes have minor clinical significance in
the presence of PI therapy [22]. Similarly, NRTI-asso-
ciated lipodystrophy, and peripheral fat wasting in the
absence of visceral fat accumulation in general ('pure
lipoatrophy'), is not associated with significant hyper-
insulinaemia, insulin resistance, or the dyslipidaemic
profile that accompanies insulin resistance (that is,
elevated apolipoprotein B and VLDL cholesterol in
addition to elevated triglyceride and decreased HDL-
cholesterol levels) [2,9,23].
A study of in vivo lipid metabolism by Ware et al.
has demonstrated an increased retention time of
dietary lipid within the circulation as free fatty acid in
PI-naive patients with lipodystrophy [24]. The authors
suggested the existence of an NRTI-induced defect in
cellular uptake of fatty acids, and proposed a mecha-
nism involving the inhibition of fatty acid-binding
proteins (FABPs) that are responsible for fatty acid
uptake and intracellular trafficking [24]. Consistent
with this hypothesis, FABP mRNA levels were found to
be decreased in stavudine-treated mice [25]. Given the
postulated association between NRTIs and mitochon-
drial toxicity, it is interesting to note that FABPs are
derived from a mitochondrial precursor (mitochon-
drial aspartate aminotransferase), which requires
intramitochondrial activation before being secreted
into the cytosol [26,27].
Mechanisms of NRTI-mediated toxicity:
mitochondrial toxicity and the 'pol-γ'
NRTIs act as false substrates for the polymerase
activity of HIV reverse transcriptase, and are charac-
terized by the lack of a hydroxyl group in the 3′
position. Thus, when the activated triphosphate form
of these compounds are used by a viral (or host) poly-
merase and added to a nascent DNA chain, there is no
site of attachment for the next nucleotide, terminating
DNA synthesis at that position. While the major poly-
merase involved in nuclear
(polymerase-α) is able to discriminate effectively
against these nucleoside analogues, this ability is not
shared by the sole polymerase present in mitochondria,
DNA synthesis
polymerase-γ [28]. This polymerase performs a
number of critical functions, as mitochondria within a
cell (of which there may be hundreds) contain multiple
copies of their own (extrachromosomal) mitochon-
drial genome. The maintenance of bioenergetic
function in all metabolically active cells therefore
requires ongoing polymerase-γ-mediated mitochon-
drial (mt) DNA synthesis as well as repair (even in
post-mitotic cells, in which nuclear DNA synthesis is
negligible), creating an ongoing requirement for nucle-
oside uptake and use by mitochondria. It is perhaps
not surprising, therefore, that chronic toxicities
induced by NRTI compounds appear to be the conse-
quences of mitochondrial dysfunction.
The possible link between polymerase-γ inhibition
and lipodystrophy was first presented by Brinkman in
1999 [29], and this area has since been reviewed by
Kakuda [30] and White [31], in which the syndrome
is considered in the context of other NRTI-induced
toxicities. The basic premise of the 'pol-γ' hypothesis
is that NRTI-induced inhibition of polymerase-γ leads
to depletion of cellular mtDNA content through inhi-
bition of mtDNA synthesis. Toxicity at the cellular
and tissue level is the consequence of loss of mito-
chondrial bioenergetic function, once mtDNA levels
have fallen beyond a critical level where the produc-
tion of mtDNA-encoded protein subunits of the
mitochondrial respiratory chain [13], and RNAs (22
tRNAs and 2 rRNAs) is insufficient to meet the cell's
energy requirements.
There is an increasing understanding of the impor-
tance of mitochondrial partitioning of these drugs
(that is, their ability to enter the mitochondrial
compartment within the cell cytosol) in determining
toxicity [32], particularly following the important
discovery of a mitochondrial inner membrane trans-
porter that is able to facilitate the entry of NRTI
triphosphate derivatives into mitochondria [33].
Based on these considerations, a modified version of
the 'pol-γ' hypothesis is proposed (modifications in
italics): (1) the NRTI has the pharmacodynamic capa-
bility to enter the target cells, and subsequently to
enter the mitochondrion in either its free-drug or
phosphorylated form; (2) the target cell possesses acti-
vated cellular nucleoside kinases to mono-, di- and
subsequently triphosphorylate the NRTI, so that the
active triphosphate form of the drug is present within
the mitochondrion; (3) the triphosphorylated NRTI
can inhibit DNA polymerase-γ either by serving as a
competitive (ineffective) alternative substrate or by
chain termination of the nascent mtDNA strand (non-
competitive); (4) the target tissue has a metabolic
reliance on
mitochondrial function (rather than 'oxidative phos-
maintenance of
Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome
Page 4
The examples of zidovudine and stavudine (both
thymidine analogues) may be considered in this light,
as NRTIs of interest in relation to the lipodystrophy
syndrome (Figure 2). Structurally, the two drugs are
similar, with the important difference being desatura-
tion of the 2′ and 3′ positions of the sugar in stavudine,
and the presence of an azide group in zidovudine. Both
compounds are hydrophilic, with relatively short
plasma half-lives (1–1.5 h) [34], and thus have no
redistribution phase to adipose tissue. At the cellular
level, zidovudine and stavudine enter the cell by passive
diffusion and are then sequentially phosporylated to
mono-, di-, and finally to the active triphosphate deriv-
ative. This process involves, in turn, thymidine kinase
(TK), thymidylate kinase and pyrimidine diphosphate
kinase [35]. At the subcellular level, however, there is
evidence that these compounds differ in their ability to
enter the mitochondrial compartment, and subse-
quently to inhibit mtDNA synthesis (Figure 2).
In the thymidine activation pathway, partitioning
into cytosolic and mitochondrial compartments occurs
at two stages. TK has a cytosolic form (TK1), which is
active only in S phase of mitosis, and a mitochondrial
form (TK2), which is expressed in proportion to the
mitochondrial content of the cell and is not cell-cycle
regulated [36]. It is likely that thymidine as well as the
free-drug forms of stavudine and zidovudine are able
to cross the mitochondrial double membrane without
requiring a specific carrier [37]. The rate limiting step
for activation of zidovudine is the conversion from
zidovudine-monophosphate (MP) to zidovudine-
diphosphate (DP) by thymidylate kinase (decreased
Vmax) [38]. Subsequently, low levels of zidovudine-
triphosphate (TP) limits access to the mitochondrion
via a specific deoxynucleotide carrier [33]. Zidovudine
is a relatively weak inhibitor of polymerase-γ (Ki1–10
µM), and since steady-state whole-cell concentration of
zidovudine-TP is <0.5 µM, this suggests that zidovu-
dine at pharmacological doses fulfils the 'pol-γ'
hypothesis criteria only mildly.
Stavudine may be able to enter the mitochondrion in
its free-drug form, or in its TP form via the deoxynu-
cleotide carrier. It has a relatively high affinity for
polymerase-γ (<0.1 µM), and on this basis it could be
predicted that pharmacological doses of stavudine
have the potential to lead to inhibit polymerase-γ,
particularly in post-mitotic cells in which TK1 is inac-
At present it is difficult to reconcile the available
data regarding the important issue of intracellular (and
intramitochondrial) activation of stavudine. As shown
in Figure 2, it is clear that thymidine kinase-mediated
phosphorylation of free stavudine is the rate-limiting
step of stavudine phosphorylation, and that affinity of
this drug for TK1 is low [39]. In relation to affinity for
TK2, activity in the presence of stavudine was shown
D Nolan et al.
©2001 International Medical Press
d4T-MP d4T-DPd4T-TP
dNT carrier (IM)
Stavudine (1–5 µM)
Zidovudine (1–5 mM)
Figure 2. Mitochondrial partitioning of zidovudine and stavudine
ZDV, zidovudine; d4T, stavudine; MP, monophosphate; DP, diphosphate; TP, triphosphate; IM, inner membrane; dNT, deoxynucleotide; TK, thymidine kinase.
Page 5
to be 0.005% of that observed with an equivalent
concentration of thymidine (20 µM) by Munch-
Peteresen et al., and this has been confirmed more
recently with recombinant TK2 [36,40]. This result is
surprising, given that stavudine retains anti-HIV
activity within the pharmacological dose range in TK1-
deficient cells (IC50HIV 0.27 µM with TK, 2.5µM in
TK-deficient CEM cells) [41], and has shown efficient
phosphorylation to the active stavudine-TP form
within isolated mitochondria [42].
This discordance may relate to the fact that the TK2
gene shows multiple transcripts, and several forms of
TK2 mRNA may also be derived from alternative
splicing or by the addition of a 3′ polyadenylation
signal [36]. It is possible, therefore, that experiments to
date have not used the TK2 specific for stavudine.
Another explanation is that stavudine may act as
substrate for another mitochondrial kinase, but this
appears less likely. The other human deoxynucleoside
kinases, deoxycytidine kinase (dCK) and deoxyguano-
sine kinase (dGK), show extensive sequence identity to
TK2 and are closely related and separate from TK1
[40]. However, dCK is cytosol-specific, while mito-
chondrial dGK is unable to recognize thymine as a
base, because of the presence of a phenylalanine
residue (Phe-156) at a critical site for thymine recogni-
tion, where thymidine kinases use a tyrosine (Tyr-172)
NRTIs and lipodystrophy
Depletion of mtDNA has now been demonstrated in
subcutaneous fat samples taken from individuals with
lipodystrophy by three independent groups [44–46]
(summarized in Table 1), providing important in vivo
data of the effects of NRTIs in the putative target
tissue. Analysis of the ultrastructure of adipocytes has
also demonstrated abnormal mitochondrial forms
(whorled cristae, elongated and branched forms) as
well as a striking increase in mitochondrial organellar
size and number [44,47,48] (Figure 3). A correlation
been mitochondrial DNA depletion and increased
mitochondrial mass has been shown in one study [46],
consistent with genetically-determined mtDNA deple-
tion syndromes, in which
mitochondria appears to represent a compensatory
response directed by the nuclear genome [49]. This
may lead to a 'vicious cycle' in which increasing levels
proliferation of
Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome
Table 1. Evidence of mitochondrial DNA depletion in subcutaneous fat samples from individuals with highly active antiretroviral
therapy-associated lipodystrophy
ResearchersMethods Findings
Walker et al. (Germany) [44]32 samples: 11 with LD, 12 HIV positive,
ART positive with no LD, 8 HIV
negative controls, 1 HIV positive, ART naive
No difference in mtDNA content between
HIV-negative controls and HIV positive
patients treated with NNRTI+PI (n=4)
NRTI treatment associated with ↓mtDNA
Among ART-treated, 38% average ↓mtDNA
content in patients with LD compared with LD-
negative (P=0.04)
Southern blot analysis
Shikuma et al. (Hawaii) [45] 69 samples from 24 individuals (8 with LD)14/23 (61%) with LD had reduced/absent
mtDNA, compared with 6/20 (30%) of non-LD
controls (P=0.04), and 3/20 (15%) of HIV-
negative controls (P=0.008)
Semiquantitative assay with size fractionation of PCR No large mtDNA mutations
product on agarose gel
Mallal et al. (Australia) [46]17 samples: 5 with LD, 5 HIV positive, ART positive with
no LD, 3 HIV positive ART-naive, 4 HIV negative controls
No difference in mtDNA content between HIV-
negative and HIV positive controls
Real-time PCR-based quantitative assay MtDNA depletion associated with NRTI treat
ment (P <0.001). Within ARTpositive group,
depletion associated with LD (P=0.05, versus
Biorad microplate assay of mt protein contentAverage mtDNA content compared with
controls: LD-positive 15%, LD-negative 58%
(adjusted for mt protein mass)
LD, lipodystrophy; mt, mitochondrial; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non- nucleoside reverse transcriptase inhibitors; PI, protease inhibitor;
ART, antiretroviral treatment.
Page 6
of TK2 (expressed in proportion to mitochondrial
mass) allow the further accumulation of intramito-
chondrial NRTI derivatives. This 'proliferative'
response may also exacerbate the pathological effects
of mtDNA depletion, by further decreasing mtDNA
content relative to the mitochondrial mass and activity
that this genome must support. In this context, a study
in which cellular mtDNA content was adjusted for
mitochondrial mass (measured by mitochondrial
protein content) has shown ~85% average depletion of
mitochondrial DNA content in samples from individ-
uals with lipodystrophy, compared with controls [46];
a level of depletion that would be considered sufficient
to cause mitochondrial dysfunction. It is, however,
difficult to ascribe a 'cut-off point' at which the magni-
tude of mtDNA depletion is considered pathological,
particularly because assays of mitochondrial depletion
provide an 'average' measure of mtDNA in a tissue
sample. Hence, the extent of mtDNA depletion in indi-
vidual cells may have been underestimated, given that
cells within a tissue are heterogeneous in terms of
mtDNA content and bioenergetic status. This concept
has been referred to as the 'bioenergetic mosaic' theory
This underlines the importance of assessing the
functional consequences of mtDNA depletion (for
example, affects on mitochondrial respiratory activity)
in vivo, so that proximal effects of polymerase-γ inhi-
bition on the mitochondrial genome (decreased
mtDNA synthesis and repair) can be related to cellular
The consequences of mtDNA depletion and associ-
ated mitochondrial dysfunction have traditionally been
considered in terms of the affect on oxidative phos-
phorylation [29]. Adipose tissue, however, has a low
oxidative capacity in keeping with its role as an energy
substrate store [51]. The role of mitochondria in
adipocytes appears to be more complex and is directed
towards providing energy for triglyceride synthesis and
storage (Figure 4). Experimentally-induced mitochon-
drial dysfunction in adipocytes increases basal glucose
uptake, without influencing insulin-stimulated glucose
uptake [52]. While glycolysis is increased, however,
loss of mitochondrial membrane potential in
adipocytes correlates with a diversion from energy
storage (triglyceride synthesis and de novo fatty acid
synthesis) to energy use associated with increased
lactate production [53]. This is consistent with a body
of work suggesting that there are a number of cellular
mechanisms that are used to 'sense' the energy and fuel
status of the cell (and hence of the mitochondria)
[54–57]. In lipogenic tissues, such as adipose and liver,
a decrease in the cytosolic ATP/ADP ratio activates a
protein kinase system (AMP-activated kinase) that
diverts resources away from energy-consuming biosyn-
thetic reactions, such as triglyceride synthesis (thus
providing a fuel store that can be called on by other
cells), towards oxidative reactions that provide energy
for the ATP-depleted cell. In adipocytes, activation of
this response decreases both lipogenesis and lipolysis
Returning to the potential role of FABPs, there is an
adipose-specific form (A-FABP, also known as aP2 or
ALBP) whose activation is dependent on the mainte-
nance of the mitochondrial membrane potential [58]. It
D Nolan et al.
©2001 International Medical Press
(a) Mitochondrial proliferation with elongated mitochondrial forms within an
expanded cytoplasm is demonstrated. Redundant folds of basal lamina (arrows)
indicate loss of cellular volume, consistent with a reduction in the size of the
major intracellular triglyceride droplet. (b) Intracytoplasmic lipid droplets
(arrows) are frequent, suggestive of mobilization of triglyceride stores for lipol-
ysis and/or oxidation. These changes are also seen in 'converted adipocytes' in
β3-adrenoceptor-agonist treated rats. Mitochondrial proliferation is also
Figure 3. Ultrastructural changes in subcutaneous fat
affected by highly active antiretroviral therapy-associated
Page 7
plays a critical role in intracellular fatty acid traf-
ficking, increasing the Vmaxof free fatty acid uptake by
adipocytes [59] and directing fatty acids to nuclear
transcription factors involved in regulating lipogenesis
[60]. Through an interaction with hormone-sensitive
lipase, A-FABP also appears to direct fatty acid export
from the cell, so that liberated fatty acid may be
released rather than be made available for re-esterifica-
tion within the adipocyte [61]. While other FABPs are
likely to be involved in fatty acid uptake it may be that
there is less redundancy in relation to fatty acid export,
as A-FABP-null mice exhibit reduced lipolysis and
accumulate fatty acid intracellularly [62]. Decreased
mitochondrial activation of A-FABP, therefore, would
be predicted to reduce the efficiency of fatty acid
uptake as well as export (in keeping with the other
cellular responses to ATP depletion).
Chronic sub-lethal mitochondrial dysfunction
induced by NRTIs in adipose tissue may therefore lead
to increased glucose uptake, glycolysis and lactate
production, as well as to the accumulation of intracel-
lular fatty acids, which are directed towards oxidative
rather than biosynthetic pathways. Severe mitochon-
drial dysfunction would be predicted to produce cell
death through apoptosis following loss of bioenergetic
viability [28], while milder mitochondrial injury may
produce an adipocyte phenotype with reduced capacity
for triglyceride synthesis or fatty acid export, thus
'isolating' it from the metabolic demands of the body
as a whole. This would be consistent with the clinical
phenotype of NRTI-associated lipodystrophy, in which
loss of subcutaneous adipose mass is not accompanied
by insulin resistance or elevated apolipoprotein-B or
VLDL-cholesterol (both markers of increased fatty
acid delivery to the liver), or with the induction of
increased visceral adiposity. A reduction in Vmaxof
adipocyte fatty acid uptake may contribute to slower
extraction of fatty acid form the circulation, and there-
fore to increased opportunity for lipid exchange
between triglyceride and HDL-cholesterol resulting in
elevated triglyceride, and reduced HDL-cholesterol,
In this context, it is interesting to note that two
recent large studies have shown that in patients
receiving PI-containing HAART, those who develop
peripheral fat wasting without increased visceral fat
accumulation ('pure lipoatrophy'), triglyceride levels
are higher and insulin sensitivity is preserved compared
with those who develop a mixed syndrome in which
visceral fat accumulation is a feature [9,23]. This will
be discussed further, when the combined effects of
NRTIs and PIs are considered.
The contribution of PIs to lipodystrophy
As mentioned previously, the use of PI therapy is
strongly associated with the 'metabolic syndrome'
component of the lipodystrophy syndrome. In keeping
with the observation that the introduction of PI
therapy is associated with changes in lipid and
glucose/insulin metabolism [5–8], cessation of PI
therapy and replacement by NRTI (abacavir) or
NNRTI therapy in 'switching studies' has been shown
to improve metabolic parameters [reviewed in 1]. In
relation to body composition changes, the interaction
of NRTIs and PIs is the dominant predictor of subcu-
taneous fat wasting as well as increased visceral
adiposity in PI-containing HAART [9]. Unfortunately,
the metabolic changes that accompany long-term dual
PI therapy are not well characterized at this time.
The 'metabolic syndrome' associated with PI
therapy (Figure 5) appears to be characterized by
increased levels of triglyceride and triglyceride-rich
lipoproteins (chylomicrons and VLDL-cholesterol).
These lipid fractions are normally elevated in the post-
prandial phase, and are destined for delipidation in the
peripheral circulation by the action of endothelial
lipoprotein lipase so that fatty acids may be removed
to adipose tissue and stored (after conversion to
triglyceride). Elevated plasma triglyceride levels are
accompanied by increased total, VLDL- and IDL-
cholesterol, apolipoproteins B and CIII as well as E,
and small-dense LDL-cholesterol as well as increased
HDL3[23,63–67]. Although total LDL-cholesterol is
often not elevated, or elevations are mild, this pheno-
Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome
↑Vmax of FA uptake
Mediate FA activation of PPAR-γ
Direct FA export following liberation by HSL
•TG synthesis from FFA:
•TG synthesis from CHO:
•ATP depletionAMPK activation
↓TG synthesis (mtGPAT)
↓ Lipolysis via HSL inactivation
↑ Glucose uptake and utilization
Fatty acid trafficking
ATP Supply
Regulation of metabolism at mt outer membrane
Figure 4. Role of mitochondria in adipose tissue
Triglyceride (TG) synthesis and storage (the major functions of adipose tissue)
are energy-requiring processes. Depletion of ATP activates the AMP-activated
protein kinase pathway, which inhibits triglyceride synthesis and de novo fatty
acid synthesis from carbohydrate precursors. AMPK activation also inhibits
lipolysis (fatty acid release from the adipocyte) by a direct effect on hormone-
sensitive lipase. Hence, mitochondrial dysfunction in adipocytes limits
lipogenesis and lipolysis, and directs metabolism towards oxidation while
increasing basal glucose uptake. Mt, mitochondrial; FA, fatty acid; FFA, free
fatty acid; CHO. cholesterol; HSL, hormone-sensitive lipase; AMPK, AMP-acti-
vated kinase; mtGPAT, mitochondrial glycerol phophate acyltransferase.
Page 8
type is now known to confer excess cardiovascular risk
– an issue addressed in a previous review [1]. A case
report demonstrating the 'unmasking' of ApoE2/E2-
related dysbetalipoproteinaemia by PI therapy
(ritonavir and indinavir) highlights a possible role for
defective clearance of apolipoprotein E-containing
lipids [68].
These lipid changes are commonly accompanied by
elevated insulin levels, and increased levels of free fatty
acid have also been observed [9,64]. Dysregulated fatty
acid metabolism was also found in a study by Sekhar
et al., [69] who used stable isotope tracer techniques to
provide a comprehensive assessment of in vivo lipid
metabolism dynamics in patients receiving PI-based
HAART. Turnover of fatty acids was found to be
dramatically increased, with elevated fat oxidation and
re-esterification in adipose and liver, increased
lipolysis, and markedly decreased clearance of triglyc-
eride-enriched VLDL and chylomicrons (Figure 4).
This metabolic phenotype is typical of defective
post-prandial lipid metabolism, which in turn is inti-
mately associated with insulin resistance. A critical role
for insulin is the production of a coordinated metabolic
response to the post-prandial (or 'fed') state, so that
carbohydrates are used as the primary source of fuel
for oxidative reactions, while lipids are directed into
adipose stores for use when metabolism must rely more
heavily on fatty acids as a fuel source (in the post-
absorptive or 'fasted' state). Hence, increasing levels of
insulin following food intake increase fatty acid uptake
and triglyceride synthesis within adipocytes, and
inhibit lipolysis (free fatty acid release from triglyc-
eride) from adipose stores. A primary defect in insulin
signalling will, therefore, inevitably produce abnormal
post-prandial lipid metabolism. An alternative scenario
also exists, in which defective post-prandial lipid
metabolism may induce insulin resistance (as would be
predicted if lipoprotein-receptor-related protein (LRP)
[70], or the acylation-stimulating protein pathway [71]
were involved in pathogenesis).
The possibility that adipose tissue may be a target of
PI-mediated effects is supported by a number of in
vitro studies indicating that pharmacological doses of
PI drugs may directly induce insulin resistance in
adipocytes [72–74], as well as a defect in the late stages
of adipocyte maturation. This block in the adipocyte
differentiation programme occurs after the adoption of
adipocyte morphology, and is characterized by
decreased expression of nuclear transcription factors
C/EBP-α and PPAR-γ [72,75–77]. These studies have
also identified sterol regulatory element-binding
protein (SREBP) as a candidate factor that may
mediate these effects [72,76,78]. This endoplasmic
reticulum-derived transcription factor, common to
D Nolan et al.
©2001 International Medical Press
Dietary fat +
Apo B100
Endothelial LPL
FFA liberated
' 'Lipid oxidation'
- uptake and transport
to mitochondria
- mitochondrial β-
oxidation, utilization as
fuel by muscle, liver
Endothelial LPL
storage' as
Figure 5. Insulin resistance and lipid metabolism
Insulin resistance decreases delipidation of chylomicrons (derived from dietary fat) and VLDL-cholesterol (from hepatic processing of fatty acids) at the level of
lipoprotein lipase, which is produced and secreted by adipocytes in response to insulin (Figure 6). Increased lipolysis from adipocytes, as well as increased chylomicron
remnants, increase hepatic processing to produce VLDL-cholesterol. VLDL metabolism normally produces LDL, which is then readily cleared by LDL receptors. 'Altered',
triglyceride-enriched VLDL, however, is diverted towards the production of IDL from HDL, as well as small, dense LDL that is less effectively cleared via the LDL
receptor and is more susceptible to oxidative modification.
Page 9
adipose tissue and the liver, appears to play a critical
role in inducing the signature adipocyte response to
post-prandial insulin release. In adipocytes it is
involved (either directly or via downstream stimulation
of PPAR-γ) in increasing fatty acid uptake (lipoprotein
lipase) and fatty acid synthesis from carbohydrate
precursors (fatty acid synthase), inhibiting lipolysis
(hormone sensitive lipase), and increasing adipocyte
differentiation, as well as increasing uptake and utiliza-
tion of glucose as energy substrate (GLUT-4,
glucokinase) (Figure 6) [79–81]. Caron et al. [72] have
provided some clues to the site of a PI-induced defect
in SREBP activity, demonstrating that PI therapy inhib-
ited the translocation of active SREBP-1c from
endoplasmic reticulum and nuclear membranes to the
nucleus. They also detected altered electrophoretic
mobility of activated SREBP-1, suggesting abnormal
processing or phosphorylation of active SREBP after
proteolytic activation from its 125 kDa precursor
form. Interestingly, defective SREBP processing may
also be central to the pathogenesis of Dunnigan-type
familial partial lipodystrophy, a severe monogenic
form of insulin resistant lipodystrophy that resembles
HAART-associated lipodystrophy phenotypically [82].
The underlying genetic defect in this condition involves
mutations in the LMNA gene that encodes nuclear
lamin A, a protein involved in the organisation of the
nuclear membrane and the regulation of trafficking of
transcription factors into the nucleus. It has been
proposed that mutated LMNA products may interact
abnormally with SREBP, so that activation of nuclear
transcription factors is impaired [82] (Figure 6).
Could adipose-selective insulin resistance be central
to the PI-associated 'metabolic syndrome', and to the
interaction between NRTIs and PIs in the development
of subcutaneous fat wasting? Certainly, interest in the
possibility that adipose tissue, rather than muscle, may
be the central regulator in insulin resistance has been
revived by a number of recent observations [83]. Mice
with an adipose-specific reduction of GLUT4 (the
insulin-responsive glucose transporter) also developed
insulin resistance in muscle and liver [84], and the
subsequent isolation of resistin, an adipose-derived
protein, has provided a plausible mechanism whereby
defective adipose insulin signalling determines more
generalized insulin resistance [85].
A recognition of depot-specific differences between
subcutaneous and visceral fat is important when
considering these effects, particularly in the context of
HIV lipodystrophy in which subcutaneous fat wasting
may be accompanied by visceral fat accumulation.
Subcutaneous fat acts as a more efficient and stable fat
storage reservoir, with greater triglyceride synthetic
capacity [71] and responsiveness to insulin [86], indi-
Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome
(68kD, active)
PPAR- γ / RXR
↑ Lipogenesis
•Fatty acid synthase
•Acetyl-CoA carboxylase
•Mitochondrial GPAT
•Lipoprotein lipase
↑Adipocyte maturation
Figure 6. Sterol regulatory element-binding protein and peroxisome proliferator activated receptor γ insulin signalling pathways
in adipocytes
Sterol regulatory element-binding protein is activated by insulin, and acts to promote lipogenesis and adipocyte differentiation via multiple pathways, acting both
directly and via intranuclear activation of peroxisome proliferator activated receptor γ / retinoid-X receptor nuclear transcription factors. SREBP, sterol regulatory
element-binding protein; IRS-2, insulin receptor substrate-2; PI3-kinase, phosphotidylinositol 3-kinase; PKB, protein kinase B; PPAR-γ, peroxisome proliferator acti-
vated receptor γ; RXR, retinoid-X receptor.
Page 10
cating a bias towards lipogenesis. This is also
supported by the fact that subcutaneous preadipocytes
differentiate more readily to mature adipocytes in
response to PPAR-γ agonists [87]. Visceral adipose
tissue, on the other hand, is a more labile fat store with
increased lipid turnover and greater expression of
specific receptors for hormones that promote lipid
accumulation (cortisol) as well as lipolysis (androgens,
growth hormone, catecholamines) [88]. Lipoprotein
lipase (LPL) activity is also higher in visceral adipose
tissue in males and females [89]. Significantly,
increased fatty acid levels promote insulin resistance in
subcutaneous fat and muscle, while visceral adipose
tissue responds by increasing glucose use and GLUT4
expression (as well as PPAR-γ and CD36/fatty acid
translocase), thus channelling fatty acids towards the
visceral fat depot, presumably in an attempt to limit
lipotoxic damage to other organs [90]. Visceral fat
accumulation, then, may represent an adaptive
response to insulin resistance and dysregulated fatty
acid metabolism [91], even in the context of adipose-
specific insulin resistance. Given the role of visceral fat
as a hormonally-responsive adipose depot, the
hormonal changes that have been seen to evolve with
the development of lipodystrophy (for example,
increasing cortisol/DHEA ratios [63], changes in
growth hormone dynamics [92], and hyperandroge-
naemia in women [93]) may be primarily determined
by visceral adiposity per se, rather than its underlying
Adipocyte insulin resistance and impaired matura-
tion has been demonstrated in vitro in the presence of
indinavir, nelfinavir, ritonavir, saquinavir and ampre-
navir in the studies previously mentioned [72–77],
suggesting that this is a class effect of PIs. As previously
mentioned, ritonavir use appears to be associated with
relatively greater increases in triglyceride levels
compared with other PI drugs [10,11]. Ritonavir
therapy in HIV-negative volunteers also induced
marked elevations of triglyceride-enriched lipoproteins
over a 2-week period (increased plasma triglyceride,
VLDL cholesterol, IDL cholesterol and apolipoprotein
B compared with controls and to baseline levels,
P<0.01 for all values) [5]. Unlike other HIV-1 protease
inhibitors, ritonavir appears to have activity as a
proteasome inhibitor [94], and shows specificity for a
proteasomal pathway involved in the degradation of
SREBP-1 [95]. Accordingly, ritonavir appears to act
mainly to increase hepatic triglyceride synthesis via
increased stabilization of nuclear SREBP-1c [96],
suggesting that its hypertriglyceridaemic activity may
be due to the additive effect of hepatic and adipose
targeting of ritonavir action. Similarly, it is possible
that the rapid induction of insulin resistance in HIV-
negative volunteers after 4 weeks' exposure to
standard-dose indinavir therapy [6] may relate to the
ability of this drug to impair insulin signalling in
multiple insulin-responsive tissues, including liver [97]
and skeletal muscle [98] as well as adipose tissue. The
effects of other PI drugs are yet to be studied in these
These in vitro studies have provided some critical
insights into possible mechanisms underlying PI-
induced adverse effects. It is hoped that in vivo studies
that are informed by these results will be undertaken, in
which involved tissue (for example, adipose tissue) is
sampled and assessed. In this way, the clinical relevance
of these findings (and the relative effects of select PIs
within this class of drugs) may be determined.
Interactions of NRTIs and PIs – an
'adipocentric' model of lipodystrophy
Taken together, the proposed effects of NRTI-induced
mitochondrial dysfunction and PI-induced insulin
resistance/impaired maturation on adipocytes each
contribute to a disorganized lipid metabolism that
appears consistent with in vivo dynamic metabolism
studies [66] (Figure 7). Loss of the lipogenic and
triglyceride-storing capacity of adipose tissue is
central to this effect, so that lipid metabolism is unable
to respond appropriately to the 'fed' state.
Uncontrolled fatty acid flux represents a response to
loss of insulin signalling, producing an ongoing
'fasting' metabolic response in which fatty acid is
liberated from adipose tissue, and fat oxidation is
stimulated. While a diversion from triglyceride and
fatty acid biosynthesis to oxidative pathways within
the adipocyte appears to be common to the proposed
NRTI and PI effects, it could be predicted that NRTI-
induced mitochondrial dysfunction would lead to
decreased lipolysis, while loss of insulin sensitivity
would increase it. It is possible that the balance
between these two effects may determine if the pheno-
type is predominantly 'lipoatrophic', where NRTI
effects are prominent (with less evidence of insulin
resistance clinically, although triglyceride levels may
be higher [9,23]), or 'mixed', in which the presence of
visceral fat accumulation and insulin resistance indi-
cate that lipolysis is dysregulated and fatty acid flux is
increased ('PI effect') [9,23].
Does this model provide an explanation for the fact
that combining NRTI and PI therapy greatly increases
the risk of developing subcutaneous fat wasting
compared with the use of either drug class alone? One
clue may be provided by the adipose tissue
morphology that is seen in HAART-associated lipody-
strophy (Figure 3), in which increased mitochondrial
mass is accompanied by evidence of decreased cellular
volume (redundant basal lamina) and loss of the
D Nolan et al.
©2001 International Medical Press
Page 11
central lipid store in favour of multiloculated intracy-
toplasmic deposits [47,48]. This phenotype is also
observed in 'converted adipocytes', described by
Himms-Hagen et al. [99], in which diversion of
adipocyte metabolism towards fatty acid oxidation
(accomplished by β3-adrenoceptor agonists in this
experimental setting) produces morphological changes
in mature adipocytes consistent with those seen in
lipodystrophy. These adipocytes are also characterized
by increased expression of uncoupling protein-3
(UCP-3), a mitochondrial protein induced by
increased cellular fatty acid levels [100]. These data
suggest that increasing adipocyte oxidative metabo-
lism, as is proposed for both NRTI and PI effects may:
(1) increase adipocyte mitochondrial mass indepen-
dent of the effects of mtDNA depletion or toxicity; (2)
increase intracellular fatty acid levels; and thus (3)
invoke mechanisms designed to limit cytotoxicity
associated with excessive fatty acid concentrations.
These responses may each contribute to enhancing
tissue mitochondrial dysfunction and cellular toxicity.
In particular, there is a well characterized mechanism
whereby increased cellular fatty acid levels induce
partial 'uncoupling' of mitochondrial respiration,
involving UCP-3 as well as other members of a closely
related family of mitochondrial inner membrane anion
transporters [101]. 'Uncoupling' refers to an imperfect
correlation between substrate use (glucose and fatty
acids) and subsequent ATP production within mito-
chondria, so that excessive substrates can be 'burned'
to produce heat rather than ATP. This regulated
response minimizes the effects of excess fatty acids
(for example, increased reactive oxidative stress and
direct toxicity within mitochondria) while also
avoiding excessive ATP production (which would
inhibit multiple biochemical pathways within mito-
chondria) [101].
It may be proposed that the appropriate physiolog-
ical responses that are evoked by impaired
mitochondrial function induced by NRTIs (mediated
by AMP-activated kinase), and by insulin resistance
and increased fatty acid flux (mediated by fatty acid
induced uncoupled respiration) are incompatible, and
lead to a pathophysiological state in which the cell is
unable to achieve energy homoeostasis. In this
scenario, a 'vicious metabolic cycle' is created, in
which restoration of the ADP/ATP ratio in response to
mitochondrial dysfunction ('energy depletion') is
subverted by an ongoing demand for decreased effi-
ciency of mitochondrial respiration by increased fatty
acids ('fuel excess').
A possible clinical correlate for this hypothesis has
been provided by Kosmiski et al. [102], who demon-
strated increased resting energy expenditure (REE) in
patients receiving PI-based HAART, consistent with data
in other insulin resistant lipodystrophy syndromes.
Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome
TG Content
FFA trapping
TG synthesis
FFA trapping
TG synthesis
'NRTI effects''PI effects'
Adipose mitochondrial dysfunctionAdipose insulin resistance
Figure 7. Dynamic regulation of intracellular triglyceride content
Intracellular triglyceride stores in adipocytes are determined by the dynamic equilibrium between triglyceride synthesis (in turn dependent on fatty acid uptake or
re-esterification, and/or fatty acid synthesis from carbohydrate precursors, as well as assembly of fatty acids and glycerol to form triglyceride); and triglyceride lipol-
ysis (by hormone sensitive lipase) and export of liberated fatty acids from the cell. In the presence of mitochondrial dysfunction ('NRTI effect'), both processes are
inhibited while energy is conserved so that the adipocyte can meet its own bioenergetic requirements. This 'isolates' the cell from the demands of whole-body
metabolism, and causes a shift from energy storage (as triglyceride) to energy use, including fat oxidation. Adipose insulin resistance ('PI effect') would be predicted
to cause loss of the post-prandial insulin response in adipocytes, resulting in reduced triglyceride storage and increased fatty acid oxidation, decreased adipocyte
differentiation, and inappropriate activation of lipolysis in the post-prandial phase.
Page 12
Elevated metabolic rate in HAART recipients had been
noted in a previous report, in which no association
between immunological or virological parameters and
REE was found [103]. However, Kosmiski et al. have
demonstrated that metabolic, rather than antiviral,
effects of PI therapy appear to determine increased REE,
which was found to be ~25% higher than predicted in
patients receiving PI-based HAART with clinical
evidence of lipodystrophy and ~6% higher in those
without clinically apparent lipodystrophy [102]. This
effect was not abrogated by adjustment for the expected
influence of fat free mass. A strong negative correlation
between accurately measured insulin sensitivity and REE
was found (correlation coefficient =–0.68, P<0.005),
and subsequent logistic regression analysis suggested
that insulin resistance was the major determinant of
REE independent of any effects of therapy on body
composition (measured by DEXA scanning and lumbar
computed tomography scans).
These findings may provide in vivo evidence of fatty
acid-induced uncoupling, as increased metabolism in the
resting state is likely to represent the consequences of
uncoupled mitochondrial respiration, while accurately
measured insulin resistance would be predicted to
provide a marker of increased tissue fatty acid flux.
The role of inner mitochondrial membrane trans-
porters such as the UCPs is also interesting from the
point of view of NRTI effects. As stated previously, the
characterization of a mitochondrial deoxynucleotide
carrier with a high affinity for activated (triphosphory-
lated) NRTIs represents a major advance in this area of
research [33]. This transmembrane protein has signifi-
cant homology with other members of the
mitochondrial membrane transporter family (including
uncoupling proteins as well as transporters critical to
mitochondrial respiratory chain function such as the
ADP/ATP translocator), so it is conceivable that interac-
tions with other transporters by NRTIs could influence
fatty acid handling and mitochondrial function through
direct non-'pol-γ' mechanisms. In this context, there is a
body of evidence that zidovudine interacts with the
muscle isoform of the ADP/ATP translocator, a factor
that may have had a role in the pathogenesis of
myopathy associated with this drug [104–106]. It is
possible that direct dose-dependent NRTI effects on a
transporter preferentially distributed in adipose tissue
(for example, dicarboxylate carrier [107]) could explain
why these hydrophilic drugs affect adipocytes preferen-
Host factors
While this review has focused on the contributions of
NRTI and PI therapy to the lipodystrophy syndrome,
we do not wish to discount the important contribution
of host factors in determining susceptibility, severity
and phenotypic expression of the lipodystrophy
syndrome. For example, gender and racial origin
appear to influence the lipodystrophy phenotype, with
an increased risk of subcutaneous fat wasting among
white males, while women and non-white males
appear to be more prone to develop visceral fat accu-
mulation. This finding has been reviewed recently
[108]. It is pertinent to mention, however, that much of
the clinical data that have been presented in both this
and a previous review [1] have been obtained from
white male patient populations, and may therefore not
apply universally.
The role of host factors is also demonstrated in
studies in which polymorphisms in genes for the β3-
adrenergic receptor [109] (involved in regulating
lipolysis in visceral fat) and for tumour necrosis factor-
α cytokine [110] (which is secreted by adipocytes and
has been implicated in the pathogenesis of insulin resis-
tance [111]) have been associated with altered
lipodystrophy outcomes. In the future, it is likely that
further host factors will emerge that significantly influ-
ence susceptibility to lipodystrophy (for example, by
preventing drug-specific toxic effects such as mito-
chondrial toxicity) as well as the severity of metabolic
and/or morphologic consequences of the syndrome.
There is still much to learn of the mechanisms that are
involved in the development of both morphologic and
metabolic components of the lipodystrophy syndrome
in individuals receiving HAART, and we look forward
to the further elucidation of these factors at the cellular
and subcellular level. While the proposed 'adipocen-
tric' model is necessarily simplistic in its approach to
the interaction between NRTIs and PIs, at this point it
is sufficient to broadly explain the clinical phenotype.
There is no doubt that compensatory as well as
contributory effects in other tissues will play a role,
and that host factors also influence susceptibility to,
and phenotypic expression of, the syndrome.
Characterizing these factors will certainly provide for a
more comprehensive aetiopathogenic model.
In conclusion, NRTIs and PIs have specific affects
on metabolism that are removed from their antiviral
activity, and are synergistic in adipose tissue. The inter-
action of NRTIs and PIs induces a phenotype in which
fat storage is diminished while fat use is enhanced,
associated with loss of the usual metabolic responses to
the 'fed' state. In this setting, reduction in subcuta-
neous adipose tissue mass is likely to be a consequence
of adipose atrophy as well as adipocyte loss, while
accumulation of fat in the visceral compartment repre-
sents a response to increased fatty acid flux and insulin
D Nolan et al.
©2001 International Medical Press
Page 13
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Antiviral Therapy 6:3
Antiviralretoviral therapy and the lipodystrophy syndrome