The molecular basis of HIV-specific T cell dysfunction

Antiviral therapy (ART) that blocks the replication of HIV has enabled a remarkable improvement in the quality of life for people living with HIV. However, populations of white blood cells that specifically recognize HIV, called CD4 and CD8 T lymphocytes, remain unable to effectively combat the virus, which rapidly replicates again if the treatment is discontinued. This compels people living with HIV to continue ART throughout their lives. Moreover, chronic inflammation is often observed, associated with an increased risk of various diseases (cardiovascular, cancers, dementia, premature aging). New treatments that allow a functional cure and long-term immune control of the residual virus are therefore necessary.

In this project, we seek to identify the mechanisms that prevent the immune system from fighting efficiently against HIV, and to find ways to restore the ability of these T cells to control the virus. We aim to understand the "instruction sets" that determine the functions of these CD4 and CD8 T cells cells. Our previous studies have shown extensive differences in the gene expression of HIV-specific CD4 T cells between rare individuals who spontaneously control the virus (elite controllers, EC) and individuals with progressive infection (CP). These differences are only partially corrected by ART. We propose to investigate the molecular basis of these differences at the level of gene programming (epigenetic analyses), their expression (transcriptomic analyses), the translated proteins (flow cytometry and proteomics), and metabolic processes. We will conduct mechanistic studies of "gain of function" and "loss of function" to determine the role of some of the identified genes. The knowledge gained could contribute to new interventions to complement ART in the pursuit of an HIV cure and to reduce the risk of clinical complications.