Women bear the greatest burden of new HIV infections throughout the world. Nevertheless, our understanding of the biology underlying HIV transmission and pathogenesis in women is incomplete. The overarching goal of this PO1 proposal is to unite a dynamic research team with complementary expertise that bridges HIV molecular biology, reproductive biology, immunology, and clinical and epidemiological research to address important, unanswered questions. 1) What sites in the female reproductive tract are most involved in HIV transmission? 2) What HIV properties and host factors critically affect transmission rates? 3) How do endogenous or exogenous sex hormones impact transmission frequency and do these factors modulate innate and adaptive immune responses in the female reproductive tract that counter infection? 4) Why have all tested vaginal microbicides not only failed to stop but often caused paradoxical increases in HIV infection? 5) Can the safety of new microbicide candidates be better assessed before large scale clinical testing? We hypothesize that 1) the upper female reproductive tract represents a highly permissive but understudied portal for HIV infection, 2) specific viral (Env) and host (semen peptides) factors importantly influence the success of male-to-female HIV transmission, 3) changes in sex hormone levels (progestin-only contraception) enhance HIV transmission and menopause adversely modulates both mucosal and systemic innate and adaptive immune responses to HIV, and 4) ineffective and unsafe microbicides activate common patterns of gene expression in the upper female reproductive tract, creating a cellular milieu that favors HIV transmission. Identification of these genes will permit construction of a predictive genetic signature for """"""""microbicide harm."""""""" These hypotheses will be tested in three specific aims involving extensive cross-project collaborations.
Specific Aim 1 : To study viral and host factors regulating male-to-female transmission of HIV in the female upper genital tract (Warner Greene, MD, PhD);
Specific Aim 2 : To explore the upper female reproductive tract as a portal of HIV transmission and to assess effects of sex steroids and microbicides on these tissues (Linda Giudice, MD, PhD, and Karen Smith-McCune, MD, PhD, and Specific Aim 3: To investigate immunopathogenesis of HIV in the female reproductive tract (Barbara Shacklett, PhD). These studies will be enabled by two essential cores, the Clinical and Data Core (Ruth Greenblatt, MD) and the Administrative Core (Drs. Greene and Greenblatt).

Public Health Relevance

Together, these studies promise to greatly extend our understanding of the molecular, cellular, and immunological basis for HIV transmission and pathogenesis in women. This work could also propel future efforts aimed at developing effective biomedical approaches to interdict male-to-female transmission of HIV.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-TP-A (J2))
Program Officer
Embry, Alan C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
J. David Gladstone Institutes
San Francisco
United States
Zip Code
Martin, Jeremy W; Chen, Joseph C; Neidleman, Jason et al. (2018) Potent and rapid activation of tropomyosin-receptor kinase A in endometrial stromal fibroblasts by seminal plasma. Biol Reprod 99:336-348
Roan, Nadia R; Sandi-Monroy, Nathallie; Kohgadai, Nargis et al. (2017) Semen amyloids participate in spermatozoa selection and clearance. Elife 6:
Smith-McCune, K K; Hilton, J F; Shanmugasundaram, U et al. (2017) Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility. Mucosal Immunol 10:1270-1278
Chen, Joseph C; Hoffman, Jacquelyn R; Arora, Ripla et al. (2016) Cryopreservation and recovery of human endometrial epithelial cells with high viability, purity, and functional fidelity. Fertil Steril 105:501-10.e1
Shanmugasundaram, Uma; Hilton, Joan F; Critchfield, J William et al. (2016) Effects of the levonorgestrel-releasing intrauterine device on the immune microenvironment of the human cervix and endometrium. Am J Reprod Immunol 76:137-48
Goldfien, Gabriel A; Barragan, Fatima; Chen, Joseph et al. (2015) Progestin-Containing Contraceptives Alter Expression of Host Defense-Related Genes of the Endometrium and Cervix. Reprod Sci 22:814-28
Oh, Sam S; Galanter, Joshua; Thakur, Neeta et al. (2015) Diversity in Clinical and Biomedical Research: A Promise Yet to Be Fulfilled. PLoS Med 12:e1001918
Smith-McCune, Karen; Chen, Joseph C; Greenblatt, Ruth M et al. (2015) Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study. PLoS One 10:e0129769
Gesner, Marianne; Maiti, Mekhala; Grant, Robert et al. (2014) Fluorescence-linked Antigen Quantification (FLAQ) Assay for Fast Quantification of HIV-1 p24(Gag). Bio Protoc 4:
Roan, Nadia R; Liu, Haichuan; Usmani, Shariq M et al. (2014) Liquefaction of semen generates and later degrades a conserved semenogelin peptide that enhances HIV infection. J Virol 88:7221-34

Showing the most recent 10 out of 29 publications