Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells

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.

Natural Immunity to HIV: A Template for Vaccine Strategies

“…Interestingly, we have shown that Beninese HESN CSWs presented higher levels of IFN-α in their CVLs when compared to those observed in HIV-infected CSWs and HIV-uninfected non-CSWs [ 45 ], which could be critical to sustain immune homeostasis, antiviral activity and restriction factors such as SAMHD1, APOBEC3, or tetherin in cells at the portal of entry for the virus. Indeed, type I interferons are indispensable to protect host against viruses [ 46 ].…”

“…Type I IFNs can be triggered via TLRs 3, 7, 8 and 9 [ 48 ], and HIV ssRNA triggers TLR 7 and TLR 8 [ 15 , 46 ]. Interestingly, genital epithelial and myeloid cell populations of Beninese HESN CSWs expressed high levels of TLR 7 [ 45 ]. IL-10, which is known to promote immunoregulatory responses was elevated in the CVLs of Beninese HESNs, but lower than that observed in CVLs of HIV-infected CSWs [ 45 ].…”

“…Interestingly, genital epithelial and myeloid cell populations of Beninese HESN CSWs expressed high levels of TLR 7 [ 45 ]. IL-10, which is known to promote immunoregulatory responses was elevated in the CVLs of Beninese HESNs, but lower than that observed in CVLs of HIV-infected CSWs [ 45 ]. IL-10 levels are often elevated in the context of HIV, unfortunately the overall outcome of excessive IL-10 may well be to sustain chronic activation and dysregulation associated with HIV disease progression, and may impede on viral eradication [ 49 , 50 , 51 ].…”

Interleukin 21 (IL-21)/microRNA-29 (miR-29) axis is associated with natural resistance to HIV-1 infection

“…It is thus possible to speculate that the high production of IL-21 and, in turn, the augmented expression of miR-29 seen in HESN, could be ascribable to this cytokine. It is important to underline that, while IL-6 expression was significantly increased in HESN CD4 þ T cells both in unstimulated conditions and upon HIV-1 infection, many studies report a reduced expression of this cytokine as well as of IL-17 [37][38][39], in other HESN cohorts [40,41]. Once more, these contrasting results recall the unresolved issue of the role played by immune-activation and immune-quiescence in the HESN phenomenon.…”

Preventing HIV infection without targeting the virus: how reducing HIV target cells at the genital tract is a new approach to HIV prevention

“…HESNs from Côte d’Ivoire had lower expression of CD69+ on memory T cells and significantly lower expression of pro-inflammatory cytokines [ 31 ]. More recently, it was shown that HESNs from a cohort of FSWs in Benin had higher levels of mucosal tolerogenic myeloid cells, higher levels of regulatory T cells [ 32 ] and reduced mucosal levels of TNF-α and IFN-γ in HESNs [ 33 ].…”