Live SIV vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cellavailability

Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic’s epicentre in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We have identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer antibody production and neonatal Fc receptor (FcRn)-mediated concentration of these antibodies on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. Here we identify as a second protection correlate, blocking CD4+ T cell recruitment to inhibit local expansion of infected founder populations. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.