Virology, Nebraska Center for


Date of this Version



J Immunol. 2014 September 15; 193(6): 3126–3133


Copyright 2014 Smith et al.


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.