P51.03
Background: Despite the fact that the antiretroviral therapy (ART) successfully controls HIV-1 in most infected patients, virus latency established early upon infection impedes HIV-1 eradication. Bryostatin-1 (BRYO) in vitro inhibits HIV-1-infection of CD4+ T lymphocytes and, at the same time, reactivates HIV-1 through PKC- NF-kB pathway. The potential effects of BRYO in combination with antiretrovirals, such as maraviroc (MVC) and Atripla® (ATP) is needed to be determined in vitro prior to design clinical trials.
Methods: Jurkat-LTRGFP-R5 cell line and two latent and reactivatable HIV-1-infected J89GFP lymphocytic or THP89GFP monocytic clonal cell lines were used as latency models.
Results: BRYO reactivates HIV-1 reaching levels>80% in THP89GFP cells, even in combination with MVC or ATP. Moreover, when MVC or ATP pre-treated reporter TZM-bl cells were co-cultured with BRYO treated with THP89GFP cells, new infections of reactivated X4/R5-HIV-189.6 were inhibited 50% or 80%, respectively. Remarkably, when antiretrovirals were combined with BRYO, the combinations maintained the antiviral effect of the drug with the maximum rate of inhibition on its own. Also, BRYO-mediated downregulation of surface CD4 and CXCR4 in primary blood mononuclear cells (PBMC) was not affected when it was used along with the other antirretrovirals and no hiperactivation or high proliferation effects were observed in these PBMC. Significantly, BRYO was also tested ex vivo for HIV-1 induction in CD4+ T lymphocytes isolated from HIV-1 infected patients receiving ART and was found to exhibit potent viral induction activity.
Conclusions: This work is the first to demonstrate that antiretrovirals combinations with BRYO do not interfere in the BRYO activity neither the BRY combination with antiretrovirals interferes in the antiviral activity of the antiretrovirals. Thus, we propose BRYO to purge the viral reservoirs, and this treatment should be combined with present ART.
