RESUMO
The persistence of latently HIV-infected cellular reservoirs, despite prolonged treatment with ART (antiretroviral therapy), represents the major hurdle to virus eradication. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of ART. Therefore, a greater understanding of the molecular mechanisms regulating viral latency and reactivation should lead to rational strategies aimed at purging the latent HIV reservoirs. Our laboratory is studying elements critical for the mechanisms of viral transcriptional reactivation including: 1) the transcription factor NF-kB, which is induced by proinflammatory cytokines (such as TNFalpha) and binds to two sites kB in the HIV-1 promoter region; 2) the specific remodeling of a single nucleosome (called nuc-1 and located immediately downstream of the HIV transcription start site under latency conditions) upon activation of the HIV-1 promoter; 3) post-translational acetylation of histones and of non-histone proteins (following treatment with deacetylase inhibitors [HDACi]), which induces viral transcription and nuc-1 remodeling. Recently, we have identified a new regulatory link between the first (NF-kB) and the third (protein acetylation) element by demonstrating a strong synergistic activation of HIV-1 promoter activity by TNFalpha (an inducer of NF-kB) and HDACi. In addition to the prototypical subtype B promoter, we have observed the TNFalpha/HDACi synergism with viral promoters from subtypes A through G of the HIV-1 major group, with a positive correlation between the number of kB sites present in the respective promoters and the amplitude of the TNFalpha/HDACi synergism. Importantly, the physiological relevance of this synergism was shown on HIV-1 replication in both acutely and latently HIV-infected cell lines. Therefore, our results open new therapeutic strategies aimed at administrating deacetylase inhibitor(s) together with continuous ART in order to force viral expression and decrease the pool of latently HIV-infected cellular reservoirs.
