Antigen-Presenting Cells Represent Targets for R5 HIV-1 Infection in the First Trimester Pregnancy Uterine Mucosa

BACKGROUND: During the first trimester of pregnancy, HIV-1 mother-to-child transmission is relatively rare despite the permissivity of placental cells to cell-to-cell HIV-1 infection. The placenta interacts directly with maternal uterine cells (decidual cells) but the physiological role of the decidua in the control of HIV-1 transmission and whether decidua could be a source of infected cells is unknown. METHODOLOGY/PRINCIPAL FINDINGS: To answer to this question, decidual mononuclear cells were exposed to HIV-1 in vitro. Decidual cells were shown to be more susceptible to infection by an R5 HIV-1, as compared to an X4 HIV-1. Infected cells were identified by flow cytometry analysis. The results showed that CD14(+) cells were the main targets of HIV-1 infection in the decidua. These infected CD14(+) cells expressed DC-SIGN, CD11b, CD11c, the Fc gamma receptor CD16, CD32 and CD64, classical MHC class-I and class-II and maturation and activation molecules CD83, CD80 and CD86. The permissivity of decidual tissue was also evaluated by histoculture. Decidual tissue was not infected by X4 HIV-1 but was permissive to R5 HIV-1. Different profiles of infection were observed depending on tissue localization. CONCLUSIONS/SIGNIFICANCE: The presence of HIV-1 target cells in the decidua in vitro and the low rate of in utero mother-to-child transmission during the first trimester of pregnancy suggest that a natural control occurs in vivo limiting cell-to-cell infection of the placenta and consequently infection of the fetus

Considerations on the Relevance of Cerebral Fusiform Aneurysms Observed During HIV Infection

International audienceHuman immunodeficiency virus (HIV)-associated ectatic cerebral vasculitis (HIV-AECV) is a rare form of vasculitis with diffuse fusiform aneurysms. Its pathophysiology remains poorly understood. Although extensively described in children, it is still incompletely studied in adults. Our objective was to present five adult cases with emphasis on imaging findings and long-term evolution. From 2006 to 2014, we included 5 HIV-infected patients presenting with fusiform cerebral aneurysms. Vessels abnormalities were assessed with brain computed tomography (CT) angiography, magnetic resonance angiography (MRA) and/or digital subtraction angiography (DSA). All patients had MR assessment of the brain. Clinical and biological data were analyzed. Fusiform aneurysms of carotid terminations extending to middle and anterior cerebral arteries were bilateral in three patients and unilateral in one. More distal fusiform aneurysms were observed in four patients and saccular aneurysms in two patients, two patients suffered from ischemic lesions while none experienced hemorrhage. Unlike recent reviews, our study underlines the low hemorrhagic potential of HIV-AECV and long-term follow-up suggests a monophasic evolution under antiretroviral medication

The local environment orchestrates mucosal decidual macrophage differentiation and substantially inhibits HIV-1 replication.

International audienceMacrophages from the decidua basalis (dM), the main uterine mucosa during pregnancy, are weakly permissive to HIV-1 infection. Here, we investigated the mechanisms underlying this natural control. We show, by using freshly purified decidual macrophages and ex vivo human decidual explants, that the local decidual environment influences dM differentiation and naturally protects these cells from HIV-1 infection. Interferon (IFN)-γ, present in the decidual tissue, contributes to maintenance of the dM phenotype and restricts HIV-1 infection by mechanisms involving the cyclin-dependent kinase inhibitor p21Cip1/Waf1. We also found that activation of Toll-like receptors 7 and 8 expressed by dM reinforces the low permissivity of dM to HIV-1 by restricting viral replication and inducing secretion of cytokines in the decidual environment, including IFN-γ, that shape dM plasticity. A major challenge for HIV-1 eradication is to control infection of tissue-resident macrophages in the female reproductive tract. Our findings provide clues to the development of novel strategies to prevent HIV-1 macrophage infection

Dynamic Shift from CD85j/ILT-2 to NKG2D NK Receptor Expression Pattern on Human Decidual NK during the First Trimester of Pregnancy

International audienceDuring the first trimester of human pregnancy, Natural Killer (NK) cells of the maternal uterine mucosa (e.g. decidua) have a unique phenotype and are involved in crucial physiological processes during pregnancy. We investigated whether modifications of the NK receptor repertoire occur during the first trimester of pregnancy. We found significantly decreased expression of KIR2DL1/S1 and KIR2DL2/L3/S2 receptors, NKp30 and NKp44 activatory receptors, and the CD85j (ILT-2) inhibitory receptor. We also observed significantly increased expression of the NKG2D activatory receptor at the decidual NK cell surface. By flow cytometry, we further highlighted an evolution of NK subsets between 8 and 12 weeks of gestation, with a shift from the KIR2DL1/S1 + /KIR2DL2/L3/S2 + subset towards the double negative subset, coupled with a decrease of the CD85j + /NKG2D 2 subset in favour of the CD85j 2 /NKG2D + subset. Furthermore, cell surface expression of NK receptor ligands, including CD85j and NKG2D ligands, has been characterized by flow cytometry on decidual immune CD14 + and CD3 + cells. HLA-G, the high affinity ligand of CD85j, was detected on both cell types. In contrast, NKG2D ligands ULBP-2 ULBP-3 and MICA/B were not expressed on CD14 + and CD3 + cells, however a variable expression of ULBP-1 was observed. The ligand expression of KIR2DL1/S1 and KIR2DL2/L3/S2 was also analyzed: the HLA-C molecule was expressed at a low level on some CD14 + cells whereas it was not detected on CD3 + cell surface. NK receptor ligands are known to be also expressed on the invading placental trophoblast cells. Thus, the phenotypic evolutions of decidual NK cells described in this present study may preserve their activation/inhibition balance during the first trimester of pregnancy

Evolution of the CD85j - NKG2D dNK subset during the first trimester of pregnancy.

<p>Decidual mononuclear cells were analyzed by flow cytometry immediately after isolation. The dNK cells were defined by the CD3⁻/CD56⁺ population within the decidual cells. (A) CD85j and NKG2D co-expression was analyzed on samples taken at 57 days (early, red), 63 days (middle, blue) and 78 days of gestation samples (late, green). Representative donor analyses are shown individually and overlaid (right dot plot). (B) Linear regression for each subset, percentage within the dNK cells (Y) and day of gestation (X). The analyses were performed on decidual cells from 28 different donors, individually represented by a dot.</p

Spearman correlation coefficient (p-value) of surface expression between NK receptors (n = 28).

<p>*Bold data are statistically significant (p-value ≤0.004).</p

NK receptor repertoire evolution of dNK cells during the first trimester of pregnancy.

<p>Expression of NK receptors on decidual mononuclear cells was analyzed between 8 and 12 weeks of gestation. Graphs represent the percentage of marker expression (Y) and the day of gestation (X). The line represents the linear regression. A p-value<0.05 was significant. The analyses were performed on decidual cells from 28 different donors, individually represented by a dot.</p

Expression of the dNK receptor ligands at the surface of decidual CD3⁺ and CD14⁺ cells during the first trimester of pregnancy.

<p>Decidual mononuclear cells were analyzed by flow cytometry immediately after isolation. The analyses were gated on the CD45⁺/CD3⁺ or on the CD45⁺/CD14⁺ populations. Box-and-whisker plots represent percentages of positive cells for each ligand. Analyses were performed on decidual cells from at least 12 different donors (n = 12–15) between 8 and 12 weeks of gestation.</p