The potential role of HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppressive activity and cytotoxicity in HIV controllers

International audienc

Blunted Response to Combination Antiretroviral Therapy in HIV Elite Controllers: An International HIV Controller Collaboration

Objective: HIV “elite controllers” (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). Methods: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. Results: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63/month), followed by +0.19/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm3, the estimated mean CD4 T-cell gain during the first 12 months was 139/mm3 in VIRs and 80/mm3 in ECs (p = 0.048). Conclusions: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients

The Genome-wide Methylation Profile of CD4+ T Cells From Individuals With Human Immunodeficiency Virus (HIV) Identifies Distinct Patterns Associated With Disease Progression

Background: Human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in progression of HIV infection. However, it is also known that viral infections can modify cellular DNA methylation patterns. Therefore, changes in the methylation of CpG islands might modulate progression of HIV infection. Methods: 85 samples were analyzed: 21 elite controllers (EC), 21 HIV-infected subjects before combination antiretroviral therapy (cART) (viremic, 93,325 HIV-1 RNA copies/ml) and under suppressive cART (cART, median of 17 months, <50 HIV-1 RNA copies/ml), and 22 HIV-negative donors (HIVneg). We analyzed the methylation pattern of 485,577 CpG in DNA from peripheral CD4+ T lymphocytes. We selected the most differentially methylated gene (TNF) and analyzed its specific methylation, mRNA expression, and plasma protein levels in 5 individuals before and after initiation of cART. Results: We observed 129 methylated CpG sites (associated with 43 gene promoters) for which statistically significant differences were recorded in viremic vs HIVneg, 162 CpG sites (55 gene promoters) in viremic vs cART, 441 CpG sites (163 gene promoters) in viremic vs EC, but none in EC vs HIVneg. The TNF promoter region was hypermethylated in viremic vs HIVneg, cART, and EC. Moreover, we observed greater plasma levels of TNF in viremic individuals than in EC, cART, and HIVneg. Conclusions: Our study shows that genome methylation patterns vary depending on HIV infection status and progression profile and that these variations might have an impact on controlling HIV infection in the absence of cART

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing life-long therapy to a global population of over 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

HIV controllers : a genetically determined or inducible phenotype?

International audienceLess than 0.5% of human immunodeficiency virus-1 (HIV-1)-infected patients maintain viral load below the threshold of detection by conventional assays for many years without antiretroviral therapy. These patients are known as HIV controllers (HICs) and offer a unique opportunity to explore and unravel efficient mechanisms of defense against HIV. An intense research effort has led to identifying viral and host factors that contribute to the control of viral replication. Although the host factors appear to be the primary determinants for HIV control, different genomic, transcriptomic, and immunological profiles have been described in HICs. This supports the existence of different mechanisms of control. We review here the most significant data in the field, including our own work, in the light of a crucial question: whether the ability to achieve and maintain the control of HIV replication is linked to genetic or immunological features specific to HIC or can be induced by vaccine or therapeutic approaches in the general population

Immune Responses to Retroviruses

International audienceRetroviruses are genome invaders that have shared a long history of coevolution with vertebrates and their immune system. Found endogenously in genomes as traces of past invasions, retroviruses are also considerable threats to human health when they exist as exogenous viruses such as HIV. The immune response to retroviruses is engaged by germline-encoded sensors of innate immunity that recognize viral components and damage induced by the infection. This response develops with the induction of antiviral effectors and launching of the clonal adaptive immune response, which can contribute to protective immunity. However, retroviruses efficiently evade the immune response, owing to their rapid evolution. The failure of specialized immune cells to respond, a form of neglect, may also contribute to inadequate antiretroviral immune responses. Here, we discuss the mechanisms by which immune responses to retroviruses are mounted at the molecular, cellular, and organismal levels. We also discuss how intrinsic, innate, and adaptive immunity may cooperate or conflict during the generation of immune responses

The Yellow Brick Road towards HIV Eradication

International audienceA London patient living with HIV-1 has become the second person to achieve remission from HIV-1 infection for >1 year after receiving a bone marrow stem cell transplant from a donor with cells resistant to CCR5-tropic HIV-1 infection (Gupta et al. Nature 2019;568:244-248). This case provides important clues in the uncertain path towards an HIV cure

Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion

International audienceno abstrac

Les Contrôleurs du VIH-1 (rôle des cellules dendritiques myéloïdes et de la réponse T CD8 dans le contrôle de l infection par le VIH-1)

Les patients contrôleurs du VIH (HIC) sont capables de contrôler durablement l infection VIH sans traitement. Certains HIC (forts répondeurs :SR) ont des réponses TCD8 quantitativement et qualitativement fortes. Comprendre comment ces réponses sont générées et maintenues pourrait orienter les recherches vaccinales. D autres HIC (faibles répondeurs :WR) contrôlent la charge virale en dépit de faibles réponses TCD8, suggèrant l existence d autres mécanismes de contrôle. Cependant, la faible réponse TCD8 peut être in vivo suffisante pour le contrôle viral. Pour comprendre les mécanismes de génération et de maintien de la réponse TCD8 chez les SR, j ai fait une étude phénotypique, transcriptomique et fonctionnelle des mDC. Nos résultats révèlent un faible profil inflammatoire des mDC des HIC sans altération de leurs capacité à stimuler les LT CD8. D autre part, les mDC des HIC ont une forte capacité à capturer le VIH-1 mais une faible susceptibilité à l infection. Ceci suggère une résistance des mDC des HIC à l infection VIH et une capacité efficace à d induire des réponses T CD8 dans un contexte peu inflammatoire. Pour explorer le rôle de la réponse TCD8 dans contrôle viral chez les HIC WR, nous avons éliminé in vivo les cellules CD8 chez des macaques contrôleurs du SIV(SIC), présentant de faibles réponses TCD8. La déplétion a causé une perte du contrôle viral chez la majorité des SIC mais la reprise du contrôle n est pas associée à une expansion importante, ni une augmentation des fonctions cytotoxiques de LT CD8. L expansion homéostatique des LT CD4 en réponse à une élévation cytokiniques pourrait expliquer la perte du contrôle virale. Nos résultats suggèrent que la réponse TCD8 n explique pas à elle seule le contrôle viral chez les WR, impliquant la contribution d autres mécanismes. Dans ce contexte, nous démontrons une susceptibilité réduite des LT CD4 et les macrophages des HIC à l infection VIH-1, ce qui pourrait contribuer à limiter le réservoir et aider contrôle viralHIV-controllers (HIC) are rare patients able to control HIV replication for several years without therapy, Some HIC (strong responders: SR) have robust CD8 T response which should be induced by a vaccine, hence the importance of understanding how this response is generated and maintained in SR. However, other HICs (Weak Responders:WR) control viral load without strong CD8 T response. This suggest the presence of other mechanisms of HIV control, although it cannot be excluded the presence of an effective memory CD8 T response in WR contributing to the viral control. To understand the mechanisms of the generation and the maintenance of such strong CD8 T response in SR, we studied a phenotypic and transcriptomic profil of myeloid dendritic cells (mDC). Our results suggest a low inflammatory profil of mDC and absence of defects in pathways relevant to CD8 T response induction. Functional studies showed a strong capacity of mDC to capture HIV but low susceptibility of these cells to infection. At all, our data suggest an resistance of HIC mDC s to HIV infection with a high capacity to induce an effective CD8 T response in low infammation context. To explore the role of CD8 T response in viral control in WR, we used simien model of SIV-Controllers macaques (SIC) with weak CD8 T response. We depleted in vivo CD8+ cells of these SIC. The depletion induced a transient loss of viral control in majority of SIC. The regain of the control has not been associated with a major expansion, nor an increase of cytotoxic functions of CD8 T cells. The loss of viral control has been associated with the homeostatic expansion of CD4 T cells in response to an increase of plasma cytokines. Our results suggest that the CD8 T response can not explain alone the viral control in WR. Other mechanisms could contribute to viral control. In these lines, we have demonstrated that CD4 T cells and macrophages from HIC are relatively resistant to HIV-1 infection, which could contribute to limit the viral reservoir and help for viral controlPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF