Role of the SIRT1 deacetylase in HIV-1 pathogenesis
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 hallmark of HIV-1 infection is a progressive loss of CD4+ T lymphocytes, the natural target cells of HIV-1. It remains unclear whether this progressive loss is due to the cytopathic effect of replicating virus or whether it is due to a syndrome of general immune hyperactivation caused by HIV-1 in infected individuals. Since HIV-1 preferentially infects activated CD4+ T cells, the hyperactivation of the immune system is expected to fuel unrestricted viral growth and enhance viral replication in infected CD4+ T lymphocytes. Therefore, T cell hyperactivation during HIV-1 infection represents an important target for therapeutic intervention. 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 and is critical for the generation of new viral genomes thereby controling the generation of progeny virions. Tat also plays an important role in the induction of immune hyperactivation in infected T cells by modulating the activity of cellular genes involved in the immune function of these cells. Therefore, Tat is both a replication and a pathogenesis factor in HIV-1 infection. We have identified a new cofactor of Tat, SIRT1, which acts at the interface of HIV-1 replication and immune activation. SIRT1 binds and deacetylates Tat, which is an important step in Tat transcriptional function. In this proposal, we will further define the role of SIRT1 in HIV-1 replication and examine its expression and activity in primary CD4+ lymphocytes and macrophages. Our preliminary data show that SIRT1 is strongly expressed in activated peripheral blood lymphocytes isolated from uninfected donors. We will examine its expression in HIV-1 infected cells and will test the replication capacity of infectious HIV-1 in activated lymphocytes in which SIRT1 expression is suppressed by RNA interference or SIRT1 activity is blocked by the new inhibitor drug. SIRT1 has previously been shown to deacetylate the transcription factor NF-kappa B/p65, a key regulator of the immune response. Acetylated p65 represents the active form of the transcription factor, while deacetylation inhibits its activity. Our preliminary data show that Tat binding to SIRT1 inhibits the deacetylation of other SIRT1 targets and induces hyperacetylation of p65 in cells. We speculate that the unique interplay between Tat and SIRT1 could play a central role in HIV-1 pathogenesis and could explain the dual role of Tat as a regulator of viral replication and an inducer of cellular hyperactivation. While SIRT1 supports Tat’s transcriptional activity on the viral promoter, its negative effect on T cell activation is neutralized by Tat and transformed into a positive effect through p65 hyperacetylation. We aim to study the role of SIRT1 in T cell activation as well as in viral replication in primary target cells of HIV-1. We will define the molecular mechanisms of Tat inhibition of SIRT1 activity and will examine whether SIRT1 is involved in the hyperactivation of p65 responsive genes in the presence of Tat. We anticipate that these studies will conclusively show whether SIRT1 is a necessary factor for Tat function and HIV replication in activated CD4+ T cells. They will further increase our understanding of T cell hyperactivation during HIV infection and explore the potential of SIRT1 as a novel target for anti-HIV-1 therapy.