Contribution du réservoir macrophagique intestinal sous traitement antirétroviral au cours de l'infection par le Virus de l'Immunodéficience Simienne

Les cellules monocytaires et les macrophages sont des cibles du virus de l’immunodéficience humaine (VIH-1) et du virus de l’immunodéficience simienne (VIS). D’une part, il a été proposé que les monocytes sanguins sont essentiels dans la réponse immune intestinale. D’autre part, les cellules monocytaires circulants reconstituent et repeuplent la région intestinale, qui est la première cible du VIH-1 et du VIS. Par conséquent, les cellules monocytaires intestinales pourraient contribuer à la dissémination virale dans l’organisme mais aussi représenter un réservoir viral sous thérapie antirétrovirale (TAR). Dans ce contexte, nous avons abordé la contribution des monocytes intestinaux dans le maintien des réservoirs viraux (VRs) chez le macaque rhésus (MR) infecté par la souche SIVmac251. Nos résultats montrent que la TAR précoce contrôle efficacement l’infection virale des cellules monocytaires, aussi bien dans le sang que dans l’intestin. Parallèlement au rebond viral après l'interruption du traitement, nous avons observé l'infection précoce des monocytes, qui présentent non seulement de l'ADN viral, mais également de l'ARN viral. Ces résultats indiquent que les sous-ensembles de cellules monocytes ne peuvent pas être considérés comme des VRs majeurs sous TAR, mais peuvent contribuer à la production virale et à la dissémination du virus une fois que celui-ci est interrompu.Monocytic cells and macrophages are targets of human immunodeficiency virus (HIV-1) and simian immunodeficiency virus (SIV). On the one hand, it has been proposed that blood monocytes are essential in the intestinal immune response. On the other hand, circulating monocytic cells reconstitute and repopulate the intestinal tract, which is the primary target of HIV-1 and SIV. Therefore, intestinal monocytic cells could contribute to the viral dissemination but also represent a viral reservoir under antiretroviral therapy (ART). In this context, we discussed the contribution of intestinal monocytes in the maintenance of viral reservoirs (VRs) in rhesus macaque (RM) infected with SIVmac251. Our results show that early ART effectively controls the viral infection of monocytic cells, both in the blood and in the intestine. Along with viral rebound after treatment interruption, we have observed early infection of monocytes, which not only display viral DNA, but also viral RNA. These results indicate that subsets of monocyte cells cannot be considered as major VRs under ART, but may contribute to viral production and viral dissemination once treatment is interrupted

Distribution of Adiponectin Receptors in the Brain of Adult Mouse: Effect of a Single Dose of the Adiponectin Receptor Agonist, AdipoRON, on Ischemic Stroke

Adiponectin exhibits pleiotropic effects, including anti-inflammatory, anti-apoptotic, antioxidant, and neuroprotective ones. Although some studies have documented brain expression in different rodent models of its receptors, AdipoR1 and AdipoR2, their global distribution remains incomplete. Here, we demonstrated that both AdipoR are widely distributed in the brains of adult mice. Furthermore, by double immunostaining studies, we showed that AdipoR1 and AdipoR2 are mainly expressed in neurons and blood vessels. Then, considering the wide distribution of both receptors and the neuroprotective effects of adiponectin, we tested the therapeutic effect of a single injection of the adiponectin receptor agonist, AdipoRON (5 mg.kg −1), 24 h after stroke in a model of middle cerebral artery occlusion technique (MCAO). Under our experimental conditions, we demonstrated that AdipoRON did not modulate the infarct volume, cell death, neuroinflammatory parameters including microglia activation and oxidative stress. This study suggests that a protocol based on multiple injections of AdipoRON at a higher dose after MCAO could be considered to promote the therapeutic properties of AdipoRON on the brain repair mechanism and recovery

Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27

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Early Antiretroviral Therapy Prevents Viral Infection of Monocytes and Inflammation in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

International audienceDespite early antiretroviral therapy (ART), treatment interruption is associated with viral rebound, indicating early viral reservoir (VR) seeding and absence of full eradication of human immunodeficiency virus type 1 (HIV-1) that may persist in tissues. Herein, we address the contributing role of monocytes in maintaining VRs under ART, since these cells may represent a source of viral dissemination due to their ability to replenish mucosal tissues in response to injury. To this aim, monocytes with classical (CD14+), intermediate (CD14+ CD16+), and nonclassical (CD16+) phenotypes and CD4+ T cells were sorted from the blood, spleen, and intestines of untreated and early-ART-treated simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) before and after ART interruption. Cell-associated SIV DNA and RNA were quantified. We demonstrated that in the absence of ART, monocytes were productively infected with replication-competent SIV, especially in the spleen. Reciprocally, early ART efficiently (i) prevented the establishment of monocyte VRs in the blood, spleen, and intestines and (ii) reduced systemic inflammation, as indicated by changes in interleukin-18 (IL-18) and IL-1 receptor antagonist (IL-1Ra) plasma levels. ART interruption was associated with a rebound in viremia that led to the rapid productive infection of both CD4+ T cells and monocytes. Altogether, our results reveal the benefits of early ART initiation in limiting the contribution of monocytes to VRs and SIV-associated inflammation.IMPORTANCE Despite the administration of antiretroviral therapy (ART), HIV persists in treated individuals and ART interruption is associated with viral rebound. Persistent chronic immune activation and inflammation contribute to disease morbidity. Whereas monocytes are infected by HIV/SIV, their role as viral reservoirs (VRs) in visceral tissues has been poorly explored. Our work demonstrates that monocyte cell subsets in the blood, spleen, and intestines do not significantly contribute to the establishment of early VRs in SIV-infected rhesus macaques treated with ART. By preventing the infection of these cells, early ART reduces systemic inflammation. However, following ART interruption, monocytes are rapidly reinfected. Altogether, our findings shed new light on the benefits of early ART initiation in limiting VR and inflammation

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

International audienceBackgroundIn malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive.MethodsIn a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype.FindingsCompared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity