Virus de l'immunodéficience humaine

Le virus de l'immunodéficience humaine (VIH-1 ou simplement VIH dans le langage courant ; en anglais, human immunodeficiency viruses-1 ou HIV-1) est une espèce de rétrovirus infectant l'humain et responsable du syndrome d'immunodéficience acquise (sida), qui est un état affaibli du système immunitaire le rendant vulnérable à de multiples infections opportunistes. La transmission du VIH par plusieurs fluides corporels (sang, sécrétions vaginales, sperme ou lait maternel) fait que le sida est aujourd'hui considéré comme une pandémie ayant causé la mort d'environ 32 millions de personnes entre 1981 (date de la première identification de cas de sida) et 2018. Il existe aujourd’hui des traitements antirétroviraux luttant contre le VIH en bloquant l’évolution de la maladie, et en empêchant sa transmission à un partenaire (à condition de suivre rigoureusement son traitement et d’obtenir une charge virale dite indétectable). Par conséquent la mortalité et la morbidité est fortement réduite

Evidence of dysregulation of dendritic cells in primary HIV infection

Jacques Fellay, Nan Hu, Marie Larsson

Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.

2010

A Baseline Cellular Antiviral State Is Maintained by cGAS and Its Most Frequent Naturally Occurring Variant rs610913

Jacques Fellay, Christian Axel Wandall Thorball, Shuting Xu

Upon recognition of aberrantly located DNA, the innate immune sensor cyclic GMP-AMP synthase (cGAS) activates stimulator of IFN genes (STING)/IFN regulatory factor (IRF)3-driven antiviral responses. In this study, we characterized the ability of a specific variant of the human cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted toward the possibility for an additional binding site for a potential cellular cofactor in cGAS dimers. However, cGAS(wild-type [WT]) or cGAS(P261H)-reconstituted THP-1 cGAS knockout cells shared steady-state expression of IFN-stimulated genes, as opposed to cells expressing the enzymatically inactive cGAS(G212A/S(213)A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared with cGAS knockout or cGAS(G212A/S(213)A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared with cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend toward a slightly reduced type I IFN response as compared with PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a baseline antiviral state rendering cells more refractory to IFN-stimulated gene-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the WT gene, suggesting that cGAS(P261H) and WT cGAS share a similar ability to sense viral infections in vivo.

AMER ASSOC IMMUNOLOGISTS2022

HIV host genomics in the era of effective antiretroviral therapy

Christian Axel Wandall Thorball

The introduction and widespread use of antiretroviral therapy against Human Immunodefi-ciency Virus (HIV) has had a remarkable effect on disease progression and the longevity of infected individuals. However, the establishment of a latent viral reservoir and the inability of antiretroviral compounds to purge it has resulted in HIV infection becoming a chronic disease with a high preva-lence of comorbidities, adding significant strain to the healthcare systems as well as the affected pa-tients. Human genetic variation has previously been shown to influence HIV pathogenesis as well as the risk of developing multiple common diseases in the general population. However, the influence of genetic variation on HIV positive individuals under suppressive antiretroviral therapy remains largely unknown. This thesis examines the role of human genetic variation in determining the size and long-term dy-namics of the viral reservoir, genetic risk factors for developing HIV-related non-Hodgkin lymphoma (NHL), and how genetic risk scores (GRS) can improve the prediction of chronic kidney disease (CKD) in HIV-infected individuals. Taken together, these studies delineate the role of human genetic variation in phenotypic outcomes that are highly relevant in the era of suppressive antiretroviral treatment, while also suggesting that newly developed genetic risk scores will be capable of enhancing the pre-dictive power of current clinical risk scores.

EPFL2020

A Baseline Cellular Antiviral State Is Maintained by cGAS and Its Most Frequent Naturally Occurring Variant rs610913

Jacques Fellay, Christian Axel Wandall Thorball, Shuting Xu

AMER ASSOC IMMUNOLOGISTS2022