# Symptoms of T-cell hyperactivation form the course and outcome of HIV-1

Symptoms of T-cell hyperactivation form the course and outcome of HIV-1 infection but the mechanism(s) underlying this chronic immune activation are not well understood. found in HIV-infected individuals. Introduction Immune activation is a hallmark of HIV-1 infection and a significant factor that promotes continuous viral replication and CD4+ T-cell depletion (Douek et al. 2003 Fauci et al. 1996 Lawn et al. 2001 In HIV-infected individuals levels of circulating activation markers correlate with accelerated disease progression and shortened survival. HIV infection is critically dependent on the activated state of CD4+ T cells since the virus cannot replicate efficiently in resting T cells. Quiescent T cells in blood are refractory to infection because of blocks at the level of reverse transcription and proviral integration (Chiu et al. 2005 Stevenson et al. 1990 In addition T-cell activation enhances viral transcription through the activation of various transcription factors notably nuclear factor κB (NF-κB) (Nabel and Baltimore 1987 HIV-1 infection itself manipulates the activation status of infected T cells through the expression of viral proteins including Env Nef and Tat (Chirmule and Pahwa 1996 Fackler and Baur 2002 Peruzzi 2006 Schindler et al. 2006 The viral transactivator Tat potently activates HIV transcription and binds to an RNA stem-loop structure termed TAR that spontaneously forms at the 5′ extremities of all viral transcripts (Barboric and Peterlin 2005 Tat also influences the expression of cellular genes in infected T cells. For example Tat synergizes with signals mediated via the T-cell receptor (TCR) and the CD28 coreceptor to superactivate interleukin (IL)-2 gene expression (Fortin et al. 2004 Ott et al. 1997 Westendorp et al. 1994 IL-2 is a T-cell growth factor with critical functions in lymphocyte proliferation cell survival and tolerance (Waldmann 2006 IL-2 expression is dependent on coordinated signals shipped via the TCR and coreceptors and it is tightly regulated in the transcriptional level. IL-2 can be essential during HIV disease: it primes non-activated bystander cells for disease in MG-132 the lack of antigenic excitement (Kinter et al. 1995 Unutmaz et al. 1994 IL-2 IL-15 and additional soluble elements present at lower focus in the milieu of lymphoid cells combine to improve permissiveness of na?ve Compact disc4+ T cells to HIV infection (Kreisberg MG-132 et al. 2006 As the function of Tat in viral transcription can be well researched the molecular system root its immunomodulatory results can Nfia be less very clear. Many prior reviews MG-132 have connected Tat with modified NF-κB actions (Buonaguro et al. MG-132 1994 Cota-Gomez et al. 2002 Demarchi et al. 1996 Ott et al. 1997 Ott et al. 1998 Scala et al. 1994 Westendorp et al. 1994 Westendorp et al. 1995 Furthermore to its central part in the rules from the innate and adaptive immune system responses NF-κB can be a crucial regulator of HIV transcription. The HIV-1 lengthy terminal do it again (LTR) consists of two tandem NF-κB binding sites. The experience from the prototypical NF-κB complicated (a heterodimer of p50 and p65 subunits) can be controlled through its association with inhibitory IκB substances and through different posttranslational adjustments including phosphorylation and acetylation. IκB substances complexed towards the NF-κB dimer in the cytoplasm are quickly phosphorylated polyubiquitylated and degraded after T-cell activation via the TCR permitting nuclear translocation of NF-κB. After translocation the p65 subunit goes through posttranslational adjustments including reversible acetylation from the histone acetyltransferase p300 (Chen et al. 2002 Kiernan et al. 2003 The acetylation of lysines 218 and 221 enhances DNA binding and prevents set up with IκBα and nuclear export of p65 while acetylation of lysine 310 (K310) potentiates the transcriptional activity of NF-κB. The transcriptional activity of NF-κB can be suppressed from the deacetylase actions of histone deacetylase (HDAC)-3 and SIRT1 two proteins that deacetylate p65 (Chen et al. 2001 Yeung et al. 2004 SIRT1 specifically deacetylates K310 in p65 and inhibits the anti-apoptotic function of NF-κB (Yeung et al. 2004 SIRT1 is a mammalian homologue of the yeast transcriptional repressor silent information regulator 2 (Sir2) an important factor governing longevity in yeast (Blander and Guarente 2004 Like Sir2 SIRT1 requires nicotinamide adenine dinucleotide (NAD+) as a cofactor which links its activity to the metabolic state of the cell. In addition to its enzymatic activity on histone substrates HDAC assay and radioactive acetylated histone peptides as substrates. We transfected wild type and.
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