| Serum vitamin A levels are inversely correlated with HIV-1 viremia and, in Africa, supplementation with vitamin A reduces morbidity in malnourished, infected children. Retinoic acid (RA), a bioactive metabolite of vitamin A, is known to indirectly repress replication of HIV-1 through a mechanism that requires new protein synthesis and subsequent inhibition of chromatin remodeling of the HIV-1 long terminal repeat (LTR). Transcription factor binding sites within the LTR, including those for NF-kappaB and Sp1, are required for RA mediated repression. The contribution of viral and host factors in RA mediated repression of HIV-1 in monocytes/macrophages was investigated. I found that LTR reporter constructs representing the HIV-1 subtypes (A through G) and containing natural mutations in essential transcription factor binding sites, including Sp1, were all repressible by RA in transfection experiments. Repression of LTR reporter constructs required RA pretreatment for at least 24 hours and occurred in the presence of Tat trans activator. Furthermore, RA repressed the replication of primary HIV-1 isolates representing subtypes B and C in primary human monocyte-derived macrophages (MDMs). Treatment of monocytes/macrophages with RA increased the accumulation of both unmodified and sumoylated isoforms of the HIV-1 transcriptional repressor Sp3 suggesting that it might play a role in RA-mediated repression.; The role of Toll-like receptors (TLRs) in activation of the HIV-1 LTR was investigated as a model for sexually transmitted co-infections (STI). Clinically, an increase in plasma viral load has been demonstrated in HIV-1 infected patients with acute STIs. Lipopolysaccharide (LPS) and other bacterial products bind to TLRs and induce activation of transcription factors known to regulate the LTR. The bacterial product peptidoglycan (PGN) and the STI pathogen Neisseria gonorrhoeae both activated replication of HIV-1 in monocytes and lymphocyte cultures. MAP kinase inhibitors known to block signaling through TLRs inhibited PGN- and N. gonorrhoeae -mediated activation of virus, suggesting that TLRs provide a link between bacterial products and increased virus replication.; Taken together, these data underscore the importance of investigating the pathways that relay exogenous signals to the HIV-1 LTR and modulate virus replication. |
