An urgent need exists to prevent the sexual transmission of HIV-1 to women. Worldwide, approximately 70% of all new cases are spread by sexual intercourse, with women more likely to be infected than men. The overall objective of this proposal is to define the role of the female reproductive tract (FRT) in preventing viral transmission and to understand how sex hormones modulate FRT HIV target cells to make women more susceptible to infection during the menstrual cycle. This proposal presents an innovative approach to test the hypothesis that during the "window of vulnerability", sex hormones (estradiol, progesterone) and chemical contraceptives (oral preparations, subcutaneous implants, and vaginal rings) enhance FRT HIV-target cell receptor expression and infection/ transmission while decreasing interferon-stimulated gene (ISG) expression. Defined as the period during the menstrual cycle when women are most susceptible to HIV infection due to hormonal changes, the "window of vulnerability" is the time hypothesized by us when women are most likely to be infected by HIV. This is a novel approach for understanding the nature and mechanisms of HIV infection in the FRT, by testing the hypothesis that during the "window", FRT HIV-target cell (CD4+T cells, macrophages, dendritic cells) receptor expression and infection/ transmission increases while interferon-stimulated gene (ISG) expression decreases, thus increasing the risk of HIV infection. This approach has 3 original Aims that will: 1) Define the changes in HIV receptor expression, activation and susceptibility to HIV infection of target cells (CD4+ T cells, macrophages and dendritic cells) in the vagina, cervix and uterus during the menstrual cycle;2) Examine the direct and indirect effects of sex hormones/contraceptives on HIV receptor expression and HIV-susceptibility of target cells in the FRT;and 3) Determine to what extent sex hormones/contraceptives suppress intracellular ISG anti-HIV activity and increase HIV infection of target cells in the FRT. This study is unique in tht it integrates our understanding of the endocrine system and the immune system throughout the human FRT as it relates directly to the very cells most likely to be infected by HIV. Understanding how sex hormones/contraceptives specifically enhance HIV infection by increasing HIV receptors and decreasing intracellular viral protection will provide a basis of knowledge for developing therapeutic mechanisms to prevent transmission of HIV. It further provides a much needed foundation of information that should accelerate the development of multipurpose prevention technologies designed to provide women with safe, effective means of protecting themselves simultaneously from HIV, other sexually transmitted and reproductive tract infections, and/or unintended pregnancy.

Public Health Relevance

An urgent need exists to prevent the sexual transmission of HIV-1 to women. Worldwide, approximately 70% of all new cases are spread by sexual intercourse, with women more likely to be infected than men. The object of this research is to develop a clear understanding of how sex hormones and chemical contraceptives (oral preparations, subcutaneous implants, and vaginal rings) enhance HIV infection of HIV-target cells (CD4+T cells, macrophages, dendritic cells) in the FRT during the window of vulnerability portion of the menstrual cycle when immune protection is depressed and when HIV infection most likely to occur.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI102838-02
Application #
8458046
Study Section
Special Emphasis Panel (ZHD1-DSR-W (50))
Program Officer
Veronese, Fulvia D
Project Start
2012-04-15
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$428,795
Indirect Cost
$163,698
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Patel, Mickey V; Ghosh, Mimi; Fahey, John V et al. (2014) Innate immunity in the vagina (Part II): Anti-HIV activity and antiviral content of human vaginal secretions. Am J Reprod Immunol 72:22-33
Wira, Charles R; Fahey, John V; Rodriguez-Garcia, Marta et al. (2014) Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens. Am J Reprod Immunol 72:236-58
Shen, Zheng; Fahey, John V; Bodwell, Jack E et al. (2014) Sex hormones regulate tenofovir-diphosphate in female reproductive tract cells in culture. PLoS One 9:e100863
Ghosh, Mimi; Rodriguez-Garcia, Marta; Wira, Charles R (2014) The immune system in menopause: pros and cons of hormone therapy. J Steroid Biochem Mol Biol 142:171-5
Biswas, Nabanita; Rodriguez-Garcia, Marta; Shen, Zheng et al. (2014) Effects of tenofovir on cytokines and nucleotidases in HIV-1 target cells and the mucosal tissue environment in the female reproductive tract. Antimicrob Agents Chemother 58:6444-53
Wira, Charles R; Rodriguez-Garcia, Marta; Shen, Zheng et al. (2014) The role of sex hormones and the tissue environment in immune protection against HIV in the female reproductive tract. Am J Reprod Immunol 72:171-81
Rodriguez-Garcia, M; Barr, F D; Crist, S G et al. (2014) Phenotype and susceptibility to HIV infection of CD4+ Th17 cells in the human female reproductive tract. Mucosal Immunol 7:1375-85
Rodriguez-Garcia, Marta; Patel, Mickey V; Wira, Charles R (2013) Innate and adaptive anti-HIV immune responses in the female reproductive tract. J Reprod Immunol 97:74-84
Patel, Mickey V; Fahey, John V; Rossoll, Richard M et al. (2013) Innate immunity in the vagina (part I): estradiol inhibits HBD2 and elafin secretion by human vaginal epithelial cells. Am J Reprod Immunol 69:463-74
Shen, Zheng; Fahey, John V; Bodwell, Jack E et al. (2013) Estradiol regulation of nucleotidases in female reproductive tract epithelial cells and fibroblasts. PLoS One 8:e69854

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