Abstract
We and others have shown that HIV-1 highly-exposed seronegative (HESN) female commercial sex workers (CSWs) maintain low genital inflammatory conditions to prevent HIV infection. HIV-1 interacts with toll-like receptors (TLR)-7/8 to induce interferon (IFN)-α, an important antiviral and immunomodulatory cytokine, which act together with interleukin (IL)-10, human leukocyte antigen (HLA)-G and immunoglobulin-like transcript (ILT)-4 to initiate a “tolerogenic/regulatory” anti-inflammatory loop. In view of further unravelling elements associated with natural immunity to HIV-1, we have characterised TLR-7, IFN-α, IL-10, HLA-G and ILT-4 expression profiles in the genital tract of female CSWs and HIV-1-uninfected non-CSWs from Benin. Endocervical myeloid HLA-DR+ cells from HESN CSWs expressed higher levels of IFN-α, TLR-7, IL-10 and HLA-G than those from both HIV-1-infected CSWs and HIV-1-uninfected non-CSWs. Further characterization of the endocervical myeloid HLA-DR+ cells in HESN CSWs revealed a population of “tolerogenic” CD103+ CD14+ CD11c+ myeloid cells expressing high levels of IFN-α and IL-10. Concomitantly, HESN CSWs had higher frequencies of endocervical regulatory CD4+ T-cells when compared to those from the two other groups of women. These novel findings provide strong evidence to support the implication of tolerogenic myeloid cells expressing high levels of antiviral molecules in shaping the genital mucosal immune response to prevent HIV infection.
Highlights
The female genital tract (FGT) constitutes a main portal of entry for HIV-1, and plays a critical role in protecting the host against pathogens while maintaining a tolerance to a commensal flora[2,3]
Levels of TNF-α, Rantes, IL-17A, IL-10, IL-22 and IFN-βwere lower in the cervico-vaginal lavages (CVLs) from highly-exposed seronegative (HESN) commercial sex workers (CSWs) when compared to those measured in the CVLs from HIV-1-infected CSWs (Fig. 1)
In agreement with previous studies[16,17,18,19,20,21,22], these observations show that the FGT of HESN CSWs exhibit relatively low levels of pro-inflammatory cytokines in comparison to HIV-1-infected CSWs and high levels of regulatory molecules such as IL-10 and sHLA-G in comparison to HIV-1-uninfected non-CSW women
Summary
The female genital tract (FGT) constitutes a main portal of entry for HIV-1, and plays a critical role in protecting the host against pathogens while maintaining a tolerance to a commensal flora[2,3]. Given the pivotal role GECs play in modulation of FGT mucosal integrity, it is likely that sensing through TLRs is involved in regulating the balance between tolerance vs defence, and modulating subsequent immunity[8,9,11]. Based on our previous studies[17,18,20] and others[16,19,21,22], we hypothesized that maintenance of low-inflammatory conditions in the FGT of HESN individuals helps to prevent excessive immune activation and lower HIV-1 target availability, likely maintaining the integrity of the mucosal barrier to protect from HIV-1 infection[2]. We aimed to further characterize immune cells that might be involved in the production of the low-inflammatory conditions observed in the FGT of HIV-1 HESN CSWs
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