CCR5 expression is elevated on endocervical CD4+ T cells in healthy postmenopausal women

Abstract

Background: New HIV-1 infections are increasing in older American women largely through heterosexual transmission. Activated CD4+ T cells and CCR5 expression are linked to HIV-1 susceptibility, but whether these parameters are altered in the cervix of older women is unknown.

Methods: Whole blood and in some instances endocervical brush samples were collected from healthy premenopausal (n = 22) and postmenopausal women (n = 24). Percentages of HLA-DR(DR)+CD38(38)+CD4+ T cells and HIV-1 chemokine coreceptor expression were determined by flow cytometry.

Results: Percentages of DR+38+CD4+ T cells were 6 times greater in cervix (median: 6.4%) than blood (median: 1.1%; P < 0.001) but did not differ within each compartment between premenopausal and postmenopausal women (P = 0.2). Postmenopausal women had greater percentages of CCR5+CD4+ and CCR5+DR+38+CD4+ T cells compared with premenopausal women in cervix (median: 70% vs. 42%, P = 0.005; and 80% vs. 57%; P = 0.05, respectively) and blood (medians: 22% vs. 13%, and 76% vs. 62%, respectively; P < 0.001). Postmenopausal women had more CCR5 molecules on cervical DR+38+CD4+ T cells (median: 3176) than premenopausal women (median: 1776; P = 0.02). Age and percent CCR5+CD4+ and CCR5+DR+38+CD4+ cells were linearly related in cervix (r(2) = 0.47, P < 0.001 and r(2) = 0.25, P = 0.01, respectively) and blood (r(2) = 0.20, P = 0.001 and r(2) = 0.31, P < 0.001; respectively), but confounding of age with menopause could not be excluded. Cervical CXCR4 expression did not differ substantially between premenopausal and postmenopausal women.

Conclusions: Elevated cervical CCR5 expression in postmenopausal women may increase their risk for HIV-1 acquisition. Studies are needed to confirm whether elevated CCR5 expression confers increased HIV-1 susceptibility in postmenopausal women, and if it is related to hormonal or nonhormonal effects of aging.

FIGURE 1

Representative flow cytometry plots of (A) cervical cells and (B) whole blood acquired from the lymphocyte gate of the forward-scatter versus side-scatter profile. Gates for HLA-DR, CD38, and CCR5 were set with Fluorescence Minus One (FMO) controls. CD3+CD4+ cells were defined in a dot plot then evaluated in a CD38 versus HLA-DR plot. CCR5 expression was evaluated on cells from CD3+CD4+ and CD38+HLA-DR+ quadrants using a histogram. Data were analyzed and compensated using FlowJo Software (Treestar).

FIGURE 2

Percentages of CCR5 and number of CCR5 molecules on CD4+ T-cells and DR+38+CD4+ T-cells in the whole blood (A-D) and cervix (E-H) from healthy postmenopausal and premenopausal women. Horizontal lines indicate median values.

FIGURE 3

Age and CCR5 expression on CD4+ and activated CD4+ T-cells had a significant linear relationship in the whole blood (A, B) and cervix (C,D). Lines generated by ordinary least squares regression.