Grant: Project Grant

Combined antiretroviral therapies (ART) are highly efficient in controlling HIV replication at undetectable plasma levels, therefore improving the life quality of people living with HIV (PLWH). However, ART does not eradicate HIV and treatment interruption results in rapid viral rebound, due to the persistence of proviral HIV-DNA integrated in the genome of long-lived memory CD4+ T-cells. Therefore, a life-long treatment is recommended. In addition, ART does not prevent the multiplication of the virus inside reservoirs cells (residual transcription), a process controlled mainly by host cell molecules. This residual HIV transcription maintains a state of chronic inflammation leading to the occurrence of non-AIDS co-morbidities in ART-treated PLWH. In the past years, our group identified the helper 17 (Th17) cells, a subset of CD4+ T-cells localized at mucosal sites, as being preferential sites of HIV infection/persistence during ART and we discovered a molecular signature associated with HIV multiplication in these cells. Among these potential therapeutic targets, the master regulator transcription factor RORC2 controls the differentiation and functionality of Th17 cells. This knowledge prompted the pharmaceutical company GlaxoSmithKlein (GSK) to design selective RORC2 inhibitors (antagonists, reverse agonists) for the treatment of autoimmunity, a conditions associated with exacerbated Th17 responses. Our preliminary results demonstrate that RORC2 also regulates HIV transcription in Th17 cells. Therefore, in collaboration with internationally renowned experts in Virology/Immunology and GSK, the purpose of this proposal is to determine whether RORC2 inhibitors can be used in immune therapy strategies to reduce the deleterious consequences of residual viral transcription during ART in men and women living with HIV.