HIV susceptibility factors in the human genital mucosa

Abstract

Heterosexual HIV transmission is the most common viral transmission route worldwide. To establish a persistent infection the virus needs to cross the mucosal surface of the genital tract. The genital mucosa is thus considered to be the portal of HIV entry and initial site of viral replication. A better understanding of the immunological milieu at the portal of viral entry is crucial for the development of preventive interventions.

In Paper I we investigated how herpes simplex virus 2 (HSV-2) affects the genital epithelial barrier and mucosal immune response in an HSV-2 seropositive, asymptomatic vs. HSV-2 seronegative male population in Kenya. The two study groups had comparable levels of all selected markers of inflammation and epithelial integrity, except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group, which may indicate a less robust genital epithelial barrier.

In Paper II, we investigated how the use of progesterone-based hormonal contraceptives affects the genital epithelial barrier and mucosal HIV receptor expression in healthy Swedish women. The progesterone-based intrauterine device (pIUD) group was compared to a non-hormonal contraceptive (noHC) group and a combined oral hormonal contraceptives (COC) group. Similar protein expression levels of HIV receptors and co-receptors were observed in the three study groups. However, women using pIUD displayed a thinner apical layer of the ectocervical epithelium and lower mRNA levels of the epithelial junction protein ZO-1 as compared to the control groups. These results suggest that pIUD use may weaken the ectocervical epithelial barrier against invading pathogens, such as HIV.

In Paper III, we further investigated how the use of hormonal contraceptives affects the production of antimicrobial peptides (AMPs) in different compartments of the female genital mucosa, including secretions and tissue. Women using COC had significantly lower mRNA levels of the AMPs BD-2 and trappin-2 in ectocervical tissue as compared to pIUD users. The two groups showed no differences in AMP protein expression in neither cervicovaginal secretion (CVS) nor in ectocervical tissue. These results suggest that the impact of sex hormones on local immune defences varies in tissue vs. secretions in the female genital tract.

In Paper IV we examined if epithelial thickness and /or the quantity and localization of HIV target cells in ectocervical epithelium is associated to the relative resistance of HIV exposed seronegative (HESN) women. Thus, female sex workers defined as HESN were compared to control women who were relatively new to sex-work. Our results show that the HESN phenotype is not associated with an altered epithelial thickness or with altered levels or distributions of HIV target cells in the ectocervical epithelium.

In summary, the studies characterized epithelial integrity in both the male and female genital tract, as well as the localization, distribution and quantity of immune cells and proteins in both tissue and secretions. These factors may be of importance for HIV susceptibility and was compared between study groups, characterized by various risk factors for HIV infection including HSV-2 infection, different types of hormonal contraceptive use and a phenotype of relative HIV resistance. Our results imply that the genital mucosa is a complex site and it is therefore of major importance to study the local immunological milieu in the tissues and not solely in secretions, which opens up for a much more comprehensive picture. Further, our data indicates that strengthening the genital epithelial barrier of the local genital mucosa may be a beneficial way to reduce sexual transmission of HIV, and should thus be incorporated in potential future prevention strategies against HIV infection.