Modulació de vies cel·lulars com a estratègia terapèutica en la infecció per vih

Resumen

The hallmarks of acquired immunodeficiency syndrome (AIDS) is a progressive depletion of CD4+ T cell populations in blood and a massive destruction of these cells in lymphoid tissues. Even though CD4+ T cells in blood recover progressively during the chronic phase, their destruction in lymphoid tissue continue during the course of infection and do not recover completely even with antiretroviral treatment (ART). A complex link exists between HIV-1 and the survival and death pathways. Discordant results have been reported regarding the interrelationship between the virus and these two cellular pathways. The aim of this Thesis was to evaluate the interplay between HIV and cell survival (autophagic pathway) and cell death (apoptosis) using human lymphoid tissue cultures ex vivo as a model to evaluate HIV infection. Our results showed that human lymphoid aggregated cultures (HLACs) from tonsillar tissue displayed a fully functional autophagic activity. In this system, HIV infection resulted in an increase in autophagy, however, this increase was not related with a loss of autophagic functionality. Notably, we observed that both, autophagy-enhancing or blocking drugs, were able to decrease HIV-DNA levels and viral replication. Regarding cell death, our data showed that in lymphoid tissue HIV infection induce both pyroptotic (caspase-1 activation) and apoptotic (caspase-3 activation) pathways. The inhibition of caspase activation by Q-VD-OPh (a pan-caspase inhibitor) was able to prevent HIV-induced CD4+ T cell depletion, but also HIV replication (in an envelope-independent manner) with a decrease in both total and integrated HIV DNA. In the evaluation of the mechanism of action of Q-VD-OPh, we observed that this drug was inducing a cellular antiviral state; decreasing cellular activation, decreasing mitochondrial membrane potential and increasing the type-I IFN response. All our data suggest that host-directed therapies are a promising emerging approach in addressing infectious diseases, and may have the potential to both interfere with host cell mechanisms hijacked by viruses for productive infection and boost innate immune defense mechanisms.