Repertoire of Chemokine Receptor Expression in the Female Genital Tract

Abstract

Sexually transmitted diseases, genital ulcer disease, and progesterone therapy increase susceptibility to lentivirus transmission. Infection of cells by human immunodeficiency virus (HIV) is dependent on expression of specific chemokine receptors known to function as HIV co-receptors. Quantitative kinetic reverse transcription-polymerase chain reaction was developed to determine the in vivo expression levels of CCR5, CXCR4, CCR3, CCR2b, and the cytomegalovirus-encoded US28 in peripheral blood mononuclear cells and cervical biopsies from 12 women with and without sexually transmitted diseases, genital ulcer disease, and progesterone-predominant conditions. Our data indicate that CCR5 is the major HIV co-receptor expressed in the female genital tract, and CXCR4 is the predominantly expressed HIV co-receptor in peripheral blood. CCR5 mRNA expression in the ectocervix was 10-fold greater than CXCR4, 20-fold greater than CCR2b, and 100-fold greater than CCR3. In peripheral blood, CXCR4 expression was 1.5-fold greater than CCR5, 10-fold greater than CCR2b, and 15-fold greater than CCR3. US28 was not expressed in cervical tissue despite expression in peripheral blood mononuclear cells from five individuals. CCR5 was significantly increased (p < 0.02) in biopsies from women with sexually transmitted diseases and others who were progesterone predominant. In vitro studies demonstrate that progesterone increases CCR5, CXCR4, and CCR3 expression and decreases CCR2b expression in lymphocytes and monocytes/macrophages. Characterization of chemokine receptors at the tissue level provides important information in identifying host determinants of HIV-1 transmission.

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

“…Macrophages, dendritic and CD4 + T cells that express CCR5 and, to a lesser extent CXCR4, are the main immune cells in genital and rectal subepithelial tissue and in gut-associated lymphoid tissue (60)(61)(62). The situation differs in blood, where CCR5 expression is restricted to 5% of circulating immune cells, most of them memory T cells, i.e., 15% of CD4 + T cells (63).…”

HIV-1-Specific Mucosal CD8+ Lymphocyte Responses in the Cervix of HIV-1-Resistant Prostitutes in Nairobi

“…HIV-1 can cross into the submucosa by transcytosis across a tight epithelial barrier, a process that can be inhibited by HIV-specific IgA (30). Furthermore, CD4 ϩ and CCR5 ϩ cell populations, which are susceptible to productive HIV-1 infection, are present in this region (31,32). The cervical submucosa is well-supplied with CD8 ϩ T lymphocytes, both of a memory (CD45RO ϩ ) and effector (perforin ϩ ) phenotype (33), and CD3 ϩ cytolytic activity is present in the genital tract throughout the menstrual cycle (31)(32)(33).…”

“…Furthermore, CD4 ϩ and CCR5 ϩ cell populations, which are susceptible to productive HIV-1 infection, are present in this region (31,32). The cervical submucosa is well-supplied with CD8 ϩ T lymphocytes, both of a memory (CD45RO ϩ ) and effector (perforin ϩ ) phenotype (33), and CD3 ϩ cytolytic activity is present in the genital tract throughout the menstrual cycle (31)(32)(33). Therefore, we hypothesize that HIV-1-specific cervical CTL in the submucosa may target susceptible host cells, which have undergone productive infection by HIV-1 after viral transcytosis across the epithelial tight membrane.…”

HIV‐1 co‐receptor expression and epithelial immune cells of the cervix in asymptomatic women attending a genitourinary medicine clinic

“…Previous studies have demonstrated endocervical T-cell infiltration during chlamydial infection, with a predominance of the effector memory subset [9]. Typical menstrual cycles have been found to have little effect on cellular infiltration [8], but may promote HIV co-receptor expression in resident immune cells of the genital tract [11,18].However, gaps in the collective knowledge of the in vivo cervical immunological microenvironment present on exposure to HIV-1 remain, requiring that further investigation is undertaken to inform transmission prevention [6]. At the time of the study, around 30% of asymptomatic women attending our genitourinary medicine (GUM) clinic had one or more detectable genital infections.…”