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Problem: The effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4 + T-cell frequency, phenotype, and HIV-specific T-cell responses in the endocervix and endometrium of HIV-infected women, comparing these tissues to the GIT., Method of Study: Mucosal samples and blood were obtained from 18 women: four who were HIV-positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV-uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T-cell frequency, phenotypes, and HIV-specific T-cell responses were analyzed by multiparameter flow cytometry., Results: T-cell activation, measured by CD38/HLA-DR co-expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV-specific CD8 + T-cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART., Conclusion: Our findings reveal differences in CD4 + T-cell frequencies, immune activation, and HIV-specific T-cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Problem: There is little information regarding the impact of the intrauterine device on immune parameters of the upper female reproductive tract related to risk of HIV acquisition., Method of Study: We collected cervical and endometrial samples from women using the hormonal intrauterine device to study its effects on endocervical cytokines/chemokine concentrations, phenotypic markers of T cells, responses of endometrial T cells to activation, and alterations of endometrial cellular infiltrates., Results: Hormonal intrauterine device use was associated with: increased concentrations of inflammatory cytokines/chemokines (endocervix); increased coexpression of CXCR4 and CCR5 (endocervix and endometrium); increased coexpression of CD38 and HLADR (endocervix and endometrium); increased intracellular IL-10 production after T-cell stimulation (endometrium); and increased density of T cells, most notably regulatory T cells (endometrium)., Conclusion: Hormonal intrauterine device use resulted in both inflammatory and immunosuppressive alterations. Further research is needed to determine the significance of these changes for HIV risk., (© 2016 The Authors. American Journal of Reproductive Immunology Published by John Wiley & Sons Ltd.)

Problem: The goal of this study was to investigate the phenotype and functional responsiveness of CD4(+) and CD8(+) T-cells in the upper reproductive tract of healthy premenopausal women. The lower reproductive tract is frequently studied as a site of sexually transmitted infections; however, the upper reproductive tract may also be a portal of entry and dissemination for pathogens, including HIV-1., Method of Study: Endometrial biopsy, endocervical curettage, cytobrush, and blood were collected during mid-luteal phase from 23 healthy women. T-cells were isolated and analyzed by flow cytometry., Results: As compared with their counterparts in blood, endometrial and endocervical T-cells had enhanced CCR5 expression, and were enriched for activated, effector memory cells. Endometrial T-cells were more responsive to polyclonal stimuli, producing a broad range of cytokines and chemokines., Conclusion: These findings underscore the responsiveness of endometrial T-cells to stimulation, and reveal their activated phenotype. These findings also suggest susceptibility of the upper reproductive tract to HIV-1 infection., (© 2013 John Wiley & Sons Ltd.)

The female reproductive tract is a major site of mucosa-associated lymphoid tissue and susceptibility to HIV infection, yet the tissue site(s) of infection and the impact of HIV infection on this important mucosal tissue remain poorly understood. CD4(+) T cells and other cell types expressing the major coreceptors for HIV, CCR5, and CXCR4 are abundant in both the lower reproductive tract (endocervix and vagina) and the upper tract (endocervix and uterus) and are highly susceptible to infection. Antiviral defenses in the female reproductive tract are mediated by a variety of soluble factors and by mucosal effector cells that differ phenotypically from their counterparts in blood. The immunologic characteristics of the female reproductive tract parallel those of the gut, where major HIV-related immunologic injury occurs. The susceptibility of the female reproductive tract to HIV infection and immunopathogenesis suggests important new avenues for further research., (© 2011 John Wiley & Sons A/S.)