Role of SIRT1 in T-cell Hyperactivation during HIV Infection
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The HIV-1 Tat protein is an important regulatory viral protein, expressed early after viral infection. Tat controls the rate of viral replication at the transcriptional level through binding to an RNA structure called TAR. Tat also plays an important role in the induction of immune hyperactivation in HIV-infected T cells. We have previously shown that Tat synergizes with signals mediated via the T cell receptor and the CD28 coreceptor to hyperactivate expression of interleukin-2, an important T cell regulatory cytokine. Many reports, including ours, have linked Tat with NF-kappa B. NF-kappa B is a critical regulator of innate and adaptive immune responses. The activity of the prototypical NF- kappa B complex (a heterodimer of p50 and p65 subunits) is regulated through association with inhibitory I kappa B molecules and posttranslational modifications, including acetylation of the p65 subunit by the histone acetyltransferase p300. The transcriptional activity of NF-?B is suppressed by the deacetylase activity of SIRT1, an NAD+ dependent protein deactylase that deacetylates p65. We find that Tat binds to the SIRT1 protein and impairs the ability of SIRT1 to deacetylate p65. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-kappa B-responsive genes, including interleukin-2. These studies suggest that SIRT1 is a negative regulator of T cell activation and a key element in the induction of HIV-induced immune hyperactivation. We hypothesize that activators of the SIRT1 deacetylase activity act as general suppressors of T cell activation and specifically counterbalance the Tat-induced immune hyperactivation during HIV infection. Generalized immune activation is an important pathogenetic factor in HIV infection. In HIV-infected individuals, levels of circulating activation markers correlate with accelerated disease progression and shortened survival. Symptoms of immune activation persist during antiretroviral therapy (ART), in part, because of residual viral replication in reservoirs where therapy is not effective. Our data support the concept that HIV infection itself causes hyperactivation of infected T cells. We will study the role of SIRT1 in activated CD4+ T cells, the natural targets of HIV infection. We will perform a comprehensive microarray analysis of all genes regulated by SIRT1 in activated T cells. We will further study the expression of SIRT1 target genes in HIV-infected T cells to determine whether they are hyperactivated during HIV infection. In addition, we will test the hypothesis that treatment with resveratrol, a compound found in red wine and a potent activator of the SIRT1 deacetylase activity, reverts immune hyperactivation in HIV-infected T cells and restores normal immune function. We anticipate that these studies will advance our understanding of the molecular mechanisms involved in the immune hyperactivation syndrome in HIV-infected patients. It could provide compelling evidence for the clinical use of SIRT1 activator in the treatment of immune hyperactivation in HIV-infected individuals.