Grant: Project Grant - Priority Announcement: HIV/AIDS and STBBI

Combined antiretroviral therapies (ART) are highly efficient at suppressing HIV replication, therefore improving the life quality of people living with HIV. However, ART does not eliminate HIV and if treatment is interrupted, the virus comes back quickly. The virus cannot be eliminated because it lives in a silent form in long-lived memory CD4+ T-cells, called the "viral reservoir". Thus, life-long ART treatment is currently recommended. Our group and others have shown that certain subsets of CD4+ T-cells called Th17 cells are particularly prone to become infected by HIV-1 and to become viral reservoirs. In these viral reservoirs, HIV-1 can reactivate spontaneously from time to time, starting to express some viral genes. ART cannot prevent this process because it mainly depends on the host cell machinery, whereas current ART only targets viral proteins. Low level spontaneous viral reactivation induces chronic activation of the immune system, which over time damages the heart, bones and the brain. Our objective is to identify new drug targets that reduce the size of the viral reservoir and block HIV reactivation in reservoir cells, especially in Th17 cells, with the ultimate goal of making these viral reservoirs harmless. Among these potential drug targets, we identified the master regulator transcription factor RORC2, encoded by the rorc gene. We found that inhibition of RORC2 prevents HIV-1 infection. Importantly, RORC2 is found in Th17 cells and not in the vast majority of CD4+ T cells. Therefore, this opens the possibility of specifically inhibiting infection of these cells and preventing viral reactivation in the large Th17 cell viral reservoir. In collaboration with the pharmaceutical company GlaxoSmithKlein (GSK) and internationally renowned experts in Virology/Immunology we will test if RORC2 inhibitors can be used to reduce the viral reservoirs, block spontaneous HIV-1 reactivation and eventually eliminate the virus.