The overall objective of this research is to understand the role that human female reproductive tract (FRT) epithelial cells play in innate immune protection against HIV-1. As sentinels of innate immune defense, epithelial cells throughout the reproductive tract are the first line of protection against sexually transmitted infections and are crucial for orchestrating a rapid response to potential viral pathogens. Our goal in this proposal is to test the hypothesis that epithelial cells from White-American, African- American, and Tanzanian women exhibit intracellular and secreted antiviral activity that protects the reproductive tract against HIV-1.
The specific aims of the current research project are to answer the following questions: 1) To what extent do epithelial cell secretions protect the female reproductive tract from HIV-1? 2) Do intracellular antiviral factors inhibit HIV-1 replication? 3) To what extent do candidate topical microbicides affect epithelial cell innate defenses? 4) Do epithelial cells influence the risk of HIV-1 infection of T cells and macrophages in the underlying stromal FRT? 5) Do FRT epithelial cells from Tanzanian women exhibit secreted and/or intracellular mechanisms of protection against HIV-1? We plan to investigate these questions using human primary epithelial cells from throughout the female reproductive tract and reproductive tract cell lines, since these cells are infectable by HIV-1, capable of protecting against HIV-1 infection, and responsive to sex hormones. The research described in this proposal will further our understanding of the mucosal immune responses involved in defending against HIV-1 and should lead to the identification of ways to augment protective responses. These studies should provide the basis of knowledge essential for the development of more effective microbicides and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI071761-05S1
Application #
8856913
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Veronese, Fulvia D
Project Start
2007-08-01
Project End
2014-07-31
Budget Start
2014-06-10
Budget End
2014-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$42,706
Indirect Cost
$16,344
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Wira, Charles R; Rodriguez-Garcia, Marta; Patel, Mickey V (2015) The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol 15:217-30
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
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
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
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
Haddad, Severina N; Wira, Charles R (2014) Estradiol regulation of constitutive and keratinocyte growth factor-induced CCL20 and CXCL1 secretion by mouse uterine epithelial cells. Am J Reprod Immunol 72:34-44
Rodriguez-Garcia, Marta; Biswas, Nabanita; Patel, Mickey V et al. (2013) Estradiol reduces susceptibility of CD4+ T cells and macrophages to HIV-infection. PLoS One 8:e62069
Hickey, Danica K; Fahey, John V; Wira, Charles R (2013) Mouse estrous cycle regulation of vaginal versus uterine cytokines, chemokines, α-/β-defensins and TLRs. Innate Immun 19:121-31

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