Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Abstract

The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1 BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel

“…Consistent with our published data, 9 , 18 among the PRE cohort, we found no significant differences in paired comparisons of any PK end point between the FOL (V4) and LUT phases (V5) of the menstrual cycle (all P values > 0.10, Supplemental Digital Content Figures 2a–2d, http://links.lww.com/QAI/B123 ). Therefore, when comparing end points among independent PRE and POST cohorts, we pooled the paired FOL phase (n = 20) and LUT phase TFV gel treatment concentrations (n = 20) from PRE participants (V4 + V5).…”

“…3 However, biological cofactors including exposure to exogenous hormones (reviewed in Ref. 4 ) or fluctuations in endogenous hormones 5 – 9 may be implicated in HIV-1 acquisition, transmission, and disease progression.…”

The vaginal microbiome amplifies sex hormone‐associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption

“…These cytokines are classic inflammation mediators, and CCL20 has been reported to promote HIV transmission to the FGT by recruiting HIV target cells such as CD4 T lymphocytes (eg, CCR5-expressing Th17 43 ) and Langerhans cells. 44 Studies assessing gene expression in vaginal, 45 endocervical, 46 and endometrial 47 tissues suggest a similar inflammatory profile in the LUT 45,46 and late LUT phase. 47 Additionally, a decrease in epithelial barrier repair proteins in the LUT phase might indicate a weakened epithelial barrier during this period, which was previously described to be affected in women using progestin-containing contraceptives.…”

“…44 Studies assessing gene expression in vaginal, 45 endocervical, 46 and endometrial 47 tissues suggest a similar inflammatory profile in the LUT45,46 and late LUT phase 47. In contrast, the LUT phase was characterized by upregulation of leukocyte and neutrophil recruitment pathways.…”

Hormonal Contraception and HIV-1 Acquisition: Biological Mechanisms

“…It is interesting to compare the different serum concentrations of progestins to those of endogenous progesterone. The concentration of endogenous progesterone in the serum of premenopausal women is low during the follicular phase (0.4 to 1.6 nM) ( 85 ) but rises to ∼16 to 51 nM during the luteal phase, and to ∼600 nM during pregnancy ( 25 , 85 – 87 ). However, it is difficult to predict how responses would differ for equivalent serum concentrations of progesterone as compared with progestins because multiple factors such as binding to serum proteins, pharmacokinetics, affinities, potencies, and efficacies via steroid receptors will affect the responses, as discussed in subsequent sections.…”