Monocyte Gene and Molecular Expression Profiles Suggest Distinct Effector and Regulatory Functions in Beninese HIV Highly Exposed Seronegative Female Commercial Sex Workers.

Laurence Blondin-Ladrie,Matheus Aranguren,Michel Roger,Nicolas De Montigny,Fernand Guédou,Annie-Claude Labbé,Johanne Poudrier,Michel Alary,Lyvia Fourcade,Alessandro Modica

doi:10.3390/v14020361

Abstract

We have previously reported that the female genital tract (FGT) of Beninese HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs), presented elevated frequencies of a myeloid HLA-DR+CD14+CD11c+ population presenting “tolerogenic” monocyte derived dendritic cells (MoDC) features. In order to assess whether a differential profile of monocytes may be involved in the generation of these genital MoDCs, we have herein characterized the blood monocyte compartment of Beninese HESNs (HIV-uninfected ≥ 10 years CSWs) and relevant controls (HIV-uninfected 2.5–5 years CSWs herein termed “early HESNs”), HIV-infected CSWs, and low-risk HIV-uninfected women from the general population. Transcriptomic analyses by RNA-Seq of total sorted blood monocytes demonstrate that in comparison to the control groups, HESNs present increased expression levels of FCGR2C, FCAR, ITGAX, ITGAM, CR2, CD68, and CD163 genes, associated with effector functions. Moreover, we found increased expression levels of genes associated with protection/control against SHIV/HIV such as CCL3, CCL4, CCL5, BHLHE40, and TNFSF13, as well as with immune regulation such as IL-10, Ahr, CD83, and the orphan nuclear receptor (NR)4A1, NR4A2, and NR4A3. Through multicolor flow cytometry analyses, we noticed that the frequencies of intermediate and non-classical monocyte populations tended to be elevated in the blood of HESNs, and exhibited increased expression levels of effector CD16, CD11c, CD11b, as well as regulatory HLA-G, IL-10, and IFN-α markers when compared to HIV-uninfected women and/or HIV-infected CSWs. This profile is compatible with that previously reported in the FGT of HESNs, and likely confers an enormous advantage in their resistance to HIV infection.

Highlights

Most HIV infections are acquired through heterosexual intercourse, and in sub-SaharanAfrica, 59% of new infections affect women [1]
Based on transcriptomic and multicolor flow cytometry analyses, we report that blood monocytes from highlyexposed seronegative (HESN) present elevated expression levels of NR4As, as well as anti-viral and regulatory markers when compared to other groups
Upon assessment of HLA-G surface expression levels, we clearly show that they are significantly increased by all monocyte populations of HESNs when compared to women from the general population and HIV-infected commercial sex workers (CSWs) (Figure 5A–D)

Summary

Introduction

Most HIV infections are acquired through heterosexual intercourse, and in sub-SaharanAfrica, 59% of new infections affect women [1]. The authors and others have established cohorts of heavily HIV-exposed African female commercial sex workers (CSWs), in which some women remain HIV-uninfected after more than 7 years of active sex work [2]. The study of these HIV-1 highly-exposed seronegative (HESN) women, who constitute a model of natural immunity to HIV, provides an exceptional opportunity to determine important clues for the development of preventive strategies, which at the moment, remain the best solutions to eradicate the pandemic. Beninese HESNs presented elevated frequencies of an endocervical myeloid HLA-DR+CD14+CD11c+ population, expressing high levels of anti-viral (TLR7, IFN-α) and immunoregulatory (IL-10, HLA-G, ILT4) molecules [5]. We found elevated frequencies of endocervical T regulatory (Treg) and Tr1 (CD49b+LAG3+)

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