Summary Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation, however their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings may be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.

Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer, and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases and cancer. We analyzed biopsies from patients with HPV- associated cervical intraepithelial neoplasia (CIN) grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3+ T cells, predominantly CD4+ T cells in human, and CD4+ and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.

We recently demonstrated that CD1d-restricted NKT cells resident in skin can inhibit CD8 T cell-mediated graft rejection of human papillomavirus (HPV) E7-expressing skin, through an IFN-γ dependent mechanism. Here we examine the role of systemically-derived NKT cells in regulating rejection of skin grafts expressing viral proteins. In lymph nodes draining transplanted skin, antigen-specific CD8 T cell proliferation, cytokine production and cytotoxic activity was impaired by NKT cells. NKT cell suppression was mediated via CD11c+ dendritic cells. Inhibition of CD8 T cell function did not require Foxp3+ regulatory T cells, or NKT cell-secreted IFN-γ, IL-10 or IL-17. Thus, following skin grafting or immunization with HPV-E7 oncoprotein, NKT cells reduce the capacity of draining lymph node resident APC to cross-present antigen to CD8 T cell precursors, as evidenced by impaired expansion and differentiation to antigen-specific CD8 T effector cells. Therefore, in the context of viral antigen challenge in the skin, systemic NKT cells limit the capacity for effective priming of adaptive immunity.