Despite the inefficiency of HIV transmission and the availability of methods to prevent HIV transmission, 2.6 million individuals acquire HIV infections every year. Although the CAPRISA Phase III trial found that tenofovir microbicide decreased HIV infection in women, the follow-up VOICE Phase III trial of the same microbicide gel failed to demonstrate any protection. Thus, in order to develop consistently effective interventions that can prevent HIV acquisition a more detailed understanding of the biology of HIV transmission populations most at risk for infection. The presence or absence of genital inflammation is of fundamental importance since and epidemiologic studies suggest that the risk of acquiring HIV-1 infection is increased in women with cervicovaginal inflammation induced by sexually transmitted infections especially HSV-2. However, despite the epidemiologic associations and supporting circumstantial evidence, it is not possible to directly determine the effects of genital inflammation on HIV transmission in humans. This project will use a non-human primate (NHP) model to provide a detailed understanding of the role of HSV2 induced genital inflammation in HIV transmission and dissemination after vaginal exposure. We have defined the target cells and dissemination pathways and the number and nature of founder SIV variants after vaginal SIVmac251 exposure. However, all these studies have been conducted with mature macaques chosen without regard to levels of pre-existing genital inflammation. Inflammation may affect critical parameters in HIV transmission and pathogenesis that, in turn can alter the ability of a vaccine or microbicide to prevent HIV transmission. These parameters include the dose of HIV required to infect an individual and the rate of HIV dissemination from the genital tract to systemic tissues. Once the virology of vaginal SIV transmission in the setting of genital inflammation is characterized, then this NHP model will be useful for testing candidate vaccines and microbicides designed to prevent HIV transmission. Moreover, in this proposal we will develop and test the hypothesis that combining antimicrobial therapy and topical anti-inflammatory agents will reduce the effect of genital inflammation on transmission.

Public Health Relevance

The proposed studies will determine the extent to which HSV-2 induced genital inflammation increases susceptibility to SIV infection and shortens the time period from infection to peak virus levels in blood which would directly affect the ability of vaccine-induced immune responses to prevent HIV transmission. We will also develop and test strategies that combine antimicrobial therapy and topical anti-inflammatory agents to reduce the effect of HSV-2 induced genital inflammation on transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098488-03
Application #
8842922
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Kuo, Lillian S
Project Start
2013-06-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618