Project Details
Description
SUMMARY
HIV affects more women than any other life-threatening infectious agent. It is most often sexually transmitted,
where virus must evade the genital mucosal barrier to cause systemic infection. Clinical studies suggest HIV
more easily penetrates this defense among women using the injectable progestin depot-medroxyprogesterone
acetate (DMPA). Offering biological plausibility for this possibility, our research group showed that DMPA
promoted mouse susceptibility to HSV-2 infection by reducing expression of the cell-cell adhesion molecule
desmoglein-1 (DSG1) and increasing genital mucosal permeability. DMPA similarly boosted susceptibility of
humanized mice to genital HIV infection. Identifying a potential mechanism for these results, we found DMPA
treatment of mice lowered vaginal levels of ephrin A3 (EFNA3); an estrogen (E) receptor target gene shown to
promote DSG1 expression in epithelial tissue. Providing clinical relevance for our findings, we showed women
initiating DMPA use display changes in ectocervical DSG1 expression and mucosal permeability identical to
those seen in mice. Likewise, pharmacologically relevant DMPA doses comparably enhanced genital mucosal
permeability in rhesus macaques (RMs). These data newly reveal DMPA impairs mucosal barrier protection.
However, using a humanized mouse model of HIV infection, we also uncovered that combined treatment with
DMPA and intravaginal (ivag) E blocks virus acquisition by enhancing genital mucosal integrity. These results
thus identified an unexpected advantage of hormonal contraceptive strategies that combine use of exogenous
progestin and E (i.e., they avert loss of barrier protection caused by progestin use alone). As necessary steps
in establishing this approach, this proposal will elucidate mechanisms of E-mediated enhancement of genital
mucosal barrier function and define capacity of an E-releasing ivag ring (E-IVR) to protect RMs from genital
SIV transmission. Expressly, we will use mice to define E-mediated regulation of EFNA3 pathways that induce
DSG1 expression and boost genital mucosal barrier function (Aim 1). We will formulate a RM-sized E-IVR to
deliver pharmacologically relevant drug doses, and use these rings to compare EFNA3 and DSG1 expression
and mucosal barrier function in RM treated with DMPA, DMPA and placebo IVR, or DMPA and E-IVR (Aim 2).
Finally, we will compare genital SIV transmission in RMs administered DMPA, DMPA and placebo IVR, or
DMPA and E-IVR with repetitive genital challenges with escalating inoculums of the virus (Aim 3). This work
will identify mechanisms by which E induces EFNA3 signaling pathways promoting genital epithelial integrity,
and demonstrate that E-IVRs block SIV transmission by abrogating DMPA-mediated weakening of genital
mucosal barrier function. These studies will thus deliver important new information in a highly relevant clinical
model, and justify exploration of similar contraceptive strategies in populations at high risk for HIV acquisition.
Status | Finished |
---|---|
Effective start/end date | 09/1/18 → 05/31/23 |
Funding
- National Institute of Child Health and Human Development: $704,544.00
- National Institute of Child Health and Human Development: $717,135.00
- National Institute of Child Health and Human Development: $410,473.00
- National Institute of Child Health and Human Development: $714,019.00
- National Institute of Child Health and Human Development: $674,198.00
- National Institute of Child Health and Human Development: $682,029.00
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