Critical events associated with sexual acquisition of HIV-1 occur in the genital mucosa. Increasingly, studies are finding that the inflammatory milieu in the genital mucosa has a profound impact on HIV-1 acquisition risk: induction of pro-inflammatory cytokines and chemokines through bacterial co-infections mediates increased risk of HIV-1 infection, while use of hormonal contraception may mediate influence on HIV-1 acquisition through reductions in anti-inflammatory anti-proteases. Furthermore, replicating HIV-1 and semen derived from the HIV-1 infected partner appear to stimulate host mediators in the female genital tract that also impact this genital mucosal environment. Given these relationships, a detailed description of the primary genital mucosal mediators and the mechanisms by which they influence HIV-1 acquisition risk will require quantification of these epidemiologic factors through longitudinal data from both sexual partners. This is only feasible through follow-up of HIV-1 serodiscordant couples: follow-up of both the HIV-1 infected and HIV-1 susceptible partner. Here we propose to use existing samples and data from a large clinical trial of oral tenofovir-based pre- exposure prophylaxis in African HIV-1 serodiscordant heterosexual couples (Partners PrEP) to quantify the most relevant genital mucosal mediators elicited in the context of well-characterized epidemiologic risk factors for HIV-1 infection. Our capacity to accomplish this is predicated on the detailed epidemiologic data collected from both sexual partners including laboratory viral sequence data from both partners facilitating confirmation of transmission linkage for all HIV-1 seroconversion events. We will use our archive of vaginal swabs and genital mucosal biopsies to facilitate a detailed quantification of genital mucosal mediators associated with these epidemiologic HIV-1 risk factors. Finally, we will test the capacity of specific genital tract mediators to predict HIV-1 acquisition risk using samples collected prior to HIV-1 infection from women who went on to seroconvert compared to HIV-1 exposed uninfected women. Through these studies we plan to quantify host genital tract mediators that modulate host susceptibility to HIV- 1 and the molecular pathways that generate them. Knowledge of these specific factors and their underlying mechanisms of action will facilitate development of novel adjuvants for modulating the host response to integrate with future HIV-1 prevention interventions.

Public Health Relevance

Sexual acquisition of HIV-1 is likely accentuated by inflammatory mediators released from genital tissues. Such mediators could be targets for novel, virus-independent HIV-1 prevention interventions. We propose to use existing samples and data from African HIV-1 serodiscordant heterosexual couples (one partner HIV-1 infected and the other not) to quantify the most relevant mediators and test their power to predict HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI111738-01
Application #
8704081
Study Section
Special Emphasis Panel (ZAI1-RB-A (J1))
Program Officer
Porter, Kristen A
Project Start
2014-03-05
Project End
2018-02-28
Budget Start
2014-03-05
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$569,229
Indirect Cost
$148,469
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195