Despite the success of anti-retroviral therapy both as treatment and prevention, novel scalable and low-cost vaccine and therapeutic tools remain the only solutions to definitively stop the global HIV/AIDS epidemic.
To achieve this goal, we need to understand better which responses should be elicited, including at the mucosa level, to prevent HIV infection and/or disease progression. Our approaches are to study human cohorts as well as primate and experimental models to decipher mechanisms implicated in the control of HIV infection and of chronic inflammation/activation, the critical determinants of HIV/AIDS pathogenesis.
1-INNATE MECHANISMS OF DEFENSE AGAINST HIV INFECTION
In order to better understand the mechanisms of natural control of HIV mucosal transmission at early time points, we are studying the model of uterine mucosa during pregnancy, the decidua. Indeed, 90% of the fetus from HIV-1 positive women are protected from infection, even in the absence of preventive antiretroviral therapy. We found that soluble factors and interactions between Natural Killer (dNK) cells and macrophages (dM) derived from human deciduas result in a negative control of HIV replication in vitro in dM. Furthermore, dM express SAMHD1, a restriction factor, that might be involved in their low permissivity to HIV-1 infection. Together, these mechanisms may contribute to the natural control of HIV transmission at the mucosal level. We also demonstrated that Toll-Like receptors are expressed by dNK cells and dM, are functional and may also participate to the control. In parallel, we are studying the innate immunity of the female reproductive tract in non pregnant women and in particular the impact of TLR activation in the control of HIV-1 infection in the different mucosal compartments.
We also found that a subset of circulating NK cells has a remarkable capacity to control HIV replication in dendritic cells (DCs). We identified a novel NK cell receptor ligand (S100A9) and found that NK cells stimulated by S100A9 ligand are able to control HIV replication on DC and CD4 T cells and to increase cytokine secretion and expression of NK cell receptors, which are implicated in the control of HIV replication. Using an in vitro model setup in our lab, we also showed that peripheral NK cells stimulated by HIV MVA ANRS vaccine candidate are primed to inhibit HIV replication.
2-IMPACT OF SEMEN ON IMMUNE RESPONSES IN THE FEMALE REPRODUCTIVE TRACT
Heterosexual transmission from male to female is the major route of transmission of HIV-1 and occurs via mucosa from the female reproductive tract (FRT). Semen is the main vector of transmission. Presence of semen in the reproductive tract induces physiological modifications such as leukocyte infiltration and inflammation, that are required for fertility. Such modifications could impact on the local and systemic immune responses. In collaboration with the Immuno-Virology Department at the CEA (Fontenay-aux-Roses), we are characterizing in vivo these immune responses after intravaginal inoculations of seminal plasma (SP) in female macaques and we are determining the impact on specific vaccine responses. In parallel, ex vivo exposure of mucosal explants to SP will help to dissect mechanisms involved in the modifications of the immune responses observed in vivo. This project, developed and funded by the Vaccine Research Institute, will give important information to take into consideration for the efficacy tests of vaccine and microbicide candidates.