While antiretroviral therapy (ART) is efficient at suppressing the replication of HIV, there is still no cure for HIV/AIDS. The major obstacle to HIV eradication is the persistence of latently infected memory CD4+ T-cells, which contain reversible, transcriptionally silenced viral genome integrated into their host chromosome. The development of novel strategies aimed at eliminating these reservoirs have become paramount in HIV research, if we want to achieve an HIV/AIDS CURE for the 35 millions HIV positive individuals. Our research programme is in line with current and world-wide HIV-1 cure research efforts, which focus on developing “Shock and Kill” strategies to eradicate persistent viral reservoirs by forcing HIV-1 gene expression. These approaches, have only been able to reactivate a portion of the latent reservoirs. The remaining non-induced latent reservoirs underlines the fact that, in CD4+ memory T-cells, HIV-1 gene silencing is the result of the quiescent cellular environment and the combinatorial action of host co-repressor complexes targeting the viral promoter and therefore its eradication will require a multi-targeted approach.
In this context, we are asking whether the memory T cell unique intracellular metabolic environment could participate in the establishment and maintenance of HIV-1 latency and most importantly, could dictate the response to current reactivation approach. In the first phase of our pre-clinical study, we will perform a combinatorial drug screen, targeting critical effectors of T-cell metabolism and identify compounds that on their own or in combination, can reverse latency by inducing HIV-1 gene expression using in vitro models of HIV latency. To test and select the most performant combination of latency-reversing drugs, we will conduct a validation screen with bona fide latently infected CD4+ cells from virally suppressed patients under ART. Our pre-clinical study could be the first step towards the development a significant component of a cure for HIV.
