Live attenuated vaccines such as SIV with a deleted nef gene have provided the most robust protection against subsequent vaginal challenge with wild-type (WT) SIV in the SIV-rhesus macaque model of HIV-1 transmission to women. Hence, identifying correlates of this protection could enable design of an effective HIV-1 vaccine. One such prechallenge correlate of protection from vaginal challenge has recently been identified as a system with three components: 1) IgG Abs reacting with the viral envelope glycoprotein trimeric gp41; 2) produced by plasma cells in the submucosa and ectopic tertiary lymphoid follicles in the ectocervix and vagina; and 3) concentrated on the path of virus entry by the neonatal FcR in the overlying epithelium. We now examine the mucosal production of the Ab component of this system after vaginal challenge. We show that vaginal challenge immediately elicits striking increases in plasma cells not only in the female reproductive tract but also at other mucosal sites, and that these increases correlate with low but persistent replication at mucosal sites. We describe vaginal ectopic follicles that are structurally and functionally organized similar to follicles in secondary lymphoid organs, and we provide inferential evidence for a key role of the female reproductive tract epithelium in facilitating Ab production, affinity maturation, and class switch recombination. Vaccination thus accesses an epithelial-immune system axis in the female reproductive tract to respond to exposure to mucosal pathogens. Designing strategies to mimic this system could advance development of an effective HIV-1 vaccine.
Bibliographical noteFunding Information:
This work was supported by the International AIDS Vaccine Initiative, National Institutes of Health Grants AI071306, U19 AI095985, and OD01110, and in part by federal funds from National Cancer Institute/National Institutes of Health Contract HHSN261200800001E. We thank Ron Desrosiers and Chris Miller for virus stocks, Angela Carville for expert veterinary care, Elizabeth Curran and Andrew Miller for assistance with tissue processing and analysis, SusanWestmoreland for review of the manuscript, and Colleen O''Neill and Tim Leonard for preparation of the manuscript and figures.
Copyright © 2016 by The American Association of Immunologists, Inc.