Genital HIV-1 viral load is a major predictor of sexual and perinatal HIV transmission, and strategies to decrease HIV-1 shedding while promoting vaginal health are urgently needed. We hypothesize that hydrogen peroxide-producing Lactobacillus (L. crispatus and L. jensenii), key components of the normal vaginal flora, decrease genital HIV-1 RNA and DNA shedding among HIV-1-infected women by direct viral inhibition and also by relative suppression of potentially pathogenic vaginal bacteria associated with bacterial vaginosis (BV). We propose to evaluate this hypothesis using archived cervicovaginal lavage (CVL) and cervical cytobrush samples from parallel cohorts of HIV-1-infected women in the United States and Kenya. Specifically, we will: 1. Examine the effect over time of L. crispatus, L. jensenii and L. iners presence and concentrations on HIV-1 RNA load in CVL, as well as the effect of these organisms on pro-inflammatory cytokines and other BV-associated flora. We anticipate that acquisition and/or higher concentrations of L. crispatus and L. jensenii (but not L. iners) will result in a significant decrease in CVL HIV-1 RNA, accounting for other factors such as plasma viral load and antiretroviral therapy, and that this protective effect may be mediated by down-regulation of pro-inflammatory cytokines and/or suppression of BV-associated bacteria. 2. Assess the longitudinal effect of vaginal Lactobacillus species, other BV-associated organisms, and pro-inflammatory cytokines on endocervical HIV-1 DNA quantitation, as well as endocervical HIV-1 RNA. We hypothesize that the protective effect of L crispatus and L jensenii will extend to the endocervix and will include a decrease in proliferation of HIV-1-infected cells as well as viral replication. Taken together, these aims will add to our understanding of the mechanisms by which hydrogen peroxide- producing Lactobacillus modulates HIV-1 in the female genital tract, and may add rationale for further evaluation of probiotics as a potential secondary HIV-1 prevention strategy.

Public Health Relevance

The amount of HIV in the vagina and cervix is a major predictor of HIV transmission between sex partners and from mother to child. This study will examine how Lactobacillus, an essential bacteria for vaginal health, works to decrease the amount of HIV in the female reproductive tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21AI080439-02S1
Application #
8108520
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Sharp, Gerald B
Project Start
2010-09-20
Project End
2012-08-31
Budget Start
2010-09-20
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$383,550
Indirect Cost
Name
University of Washington
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bull, Marta E; Legard, Jillian; Tapia, Kenneth et al. (2014) HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells. J Acquir Immune Defic Syndr 67:357-64
Mitchell, Caroline; Balkus, Jennifer E; McKernan-Mullin, Jennifer et al. (2013) Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women. J Acquir Immune Defic Syndr 62:143-8
Mitchell, Caroline; Balkus, Jennifer E; Fredricks, David et al. (2013) Interaction between lactobacilli, bacterial vaginosis-associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women. AIDS Res Hum Retroviruses 29:13-9
Balkus, Jennifer E; Mitchell, Caroline; Agnew, Kathy et al. (2012) Detection of hydrogen peroxide-producing Lactobacillus species in the vagina: a comparison of culture and quantitative PCR among HIV-1 seropositive women. BMC Infect Dis 12:188