HIV-1 infection leads to an immune response in the host that is thought to resolve the high levels of viremia found during the acute phase of infection. Chronic infections are possible because HIV-1 has evolved to evade the host immune response. One strategy of immune evasion used by HIV-1 is the establishment of latent infections. Vitamin A metabolites, including all-trans retinoic acid (RA), are natural repressors of HIV1 expression and may play a role in the establishment and maintenance of viral latency. RA consistently represses HIV-1 replication in primary macrophages that are stimulated by cytokines normally found in high concentrations at local sites, where infected macrophages reside in viva The overall goals of this proposal are to understand how RA represses HIV-1 expression and to determine the role of this process in latency, RA repression of HIV-1 expression is associated with an inhibition in the remodeling and histone H4 hyperacetylation of a nucleosome positioned at the start site of HIV-1 transcription. These results, and the finding that repression requires new cellular protein synthesis, support the hypothesis that RA induces a factor that specifically associates with the viral promoter and thereby prevents chromatin remodeling. The goal of this proposal is to test this hypothesis. There are two specific aims. The goal of aim I is to evaluate the role of RA as a repressor of HIV-1 replication in cytokine activated primary macrophages and to determine whether repression requires the induction of specific cellular signaling pathways. The goal of aim 2 is to evaluate the role of RA as an regulator of the HIV-1 chromatin structure in established cell lines and primary cells. RA-induced changes in nucleosome binding and the post-translational modification of histones will be examined using in vivo nucleosome mapping and footprinting as well as chromatin immunoprecipitation assays.
These aims are part of the long term goal of delineating the molecular mechanisms of retinoid-mediated repression and determining their therapeutic potential.
| Kiefer, Heather L B; Hanley, Timothy M; Marcello, Jennifer E et al. (2004) Retinoic acid inhibition of chromatin remodeling at the human immunodeficiency virus type 1 promoter. Uncoupling of histone acetylation and chromatin remodeling. J Biol Chem 279:43604-13 |
| Hanley, Timothy M; Kiefer, Heather L B; Schnitzler, Aletta C et al. (2004) Retinoid-dependent restriction of human immunodeficiency virus type 1 replication in monocytes/macrophages. J Virol 78:2819-30 |
| Brown, Xin Qian; Hanley, Timothy M; Viglianti, Gregory A (2002) Interleukin 1 beta and interleukin 6 potentiate retinoic acid-mediated repression of human immunodeficiency virus type 1 replication in macrophages. AIDS Res Hum Retroviruses 18:649-56 |
