In situ characterization of immune cells mediating potential control of HIV infection in the female genital mucosa

Heterosexual HIV transmission is the most common viral transmission route, worldwide, where young women are more susceptible to HIV infection than men. To establish a persistent infection the virus needs to cross the mucosal surface of the female genital tract (FGT). The FGT 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. Hence, in this thesis we quantified and characterized immune cells, primarily subsets of CD8+ T cell, in the FGT tissues of HIV-infected and uninfected women.

In Paper I and II, we observed that HIV-infected women displayed similar levels of CD4 expression in their ectocervix as compared to uninfected controls. However, they showed higher immune activation levels as well as signs of HIV replication in their cervix. An inflammatory environment in the genital mucosa may promote viral replication and genital shedding and thereby increase the risk of sexual HIV transmission. The HIV-infected women also had elevated levels of cervical CD8+ cells, which correlated significantly with cervical viral load. The CD8+ cells were predominantly intraepithelial CD8+ T cells and 60% of them expressed CD103 (Paper II, III). Our data thus suggests that CD8+ T cells, including tissue-resident CD8+ T cells, may be actively recruited to/or expanded in the genital mucosa of chronically HIV-infected sex workers. This implies that tissue-residing CD8+ T cells play an important role in local HIV pathogenesis. To further investigate immune responses in the FGT mucosa we assessed the expression of MAIT cells in the genital tissues of healthy women (Paper IV). FGT-derived MAIT cells preferentially localized in the ectocervical epithelium and were biased towards IL-17 and IL-22 production upon bacterial stimulation. This indicates that functional MAIT cells localized near the luminal surface of the genital mucosa may be important for the preservation of the genital barrier integrity and may act as a first line of defence against invading pathogens.

In summary, this thesis describes the localization and distribution of immune cells in the genital mucosa of HIV-infected and uninfected women. Studies described here may contribute to the knowledge needed for development of vaccination and/or microbicide strategies against HIV and other sexually transmitted infections.

List of scientific papers

I. Stable CD4 expression and local immune activation in the ectocervical mucosa of HIV- infected women. Taha Hirbod, Joshua Kimani, Annelie Tjernlund, Juliana Cheruiyot, ANNA PETROVA (GIBBS), Terry B. Ball, Nelly Mugo, Walter Jaoko, Francis A. Plummer, Rupert Kaul and Kristina Broliden. Journal of Immunology. 2013 Oct 1; 191(7):3948-54.
https://doi.org/10.4049/jimmunol.1301220

II. Presence of CD8+ T cells in the ectocervical mucosa correlates with genital viral shedding in HIV-infected women despite a low prevalence of HIV RNAexpressing cells in the tissue. ANNA GIBBS, Taha Hirbod, Qingsheng Li, Karin Bohman, Terry B. Ball, Francis A. Plummer, Rupert Kaul, Joshua Kimani, Kristina Broliden and Annelie Tjernlund. Journal of Immunology. 2014 Apr 15; 192(8):3947-57.
https://doi.org/10.4049/jimmunol.1302826

III. HIV-infected women display lower proportion of cervical and circulating CD103+ cells among CD8+ T cells, despite the overall increase in total numbers of tissue-resident CD8+ T cells in their cervical epithelium. ANNA GIBBS, Marcus Buggert, Petter Ranefall, Andrea Introini, Stanley Cheuk, Liv Eidsmo, Taha Hirbod, Terry B. Ball, Joshua Kimani, Rupert Kaul, Annika C. Karlsson, Carolina Wählby, Kristina Broliden and Annelie Tjernlund. [Manuscript]

IV. MAIT cells reside in the female genital mucosa and are biased towards IL-17 and IL-22 production in response to bacterial stimulation. ANNA GIBBS, Edwin Leeansyah, Andrea Introini, Dominic Paquin-Proulx, Klara Hasselrot, Emilia Andersson, Kristina Broliden, Johan K. Sandberg and Annelie Tjernlund. Mucosal Immunology. [Accepted]
https://doi.org/10.1038/mi.2016.30