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Cytotoxic CD8+ T Cells Expressing CXCR5 Are Detectable in HIV-1 Elite Controllers After Prolonged In Vitro Peptide Stimulation.

ABSTRACT: Antiretroviral therapy (ART) is not curative as HIV-1 persists in long-lived viral reservoirs. Consequently, patients are dependent on life-long drug adherence with possible side effects. To overcome these limitations strategies of a functional cure aim at ART free viral remission. In this study, we sought to identify detailed subsets of anti-viral CD8⁺ T cell immunity linked to natural long-term control of HIV-1 infection. Here, we analyzed HIV controllers and ART suppressed progressors for in vitro viral suppressive capacity (VSC) at baseline and after peptide stimulation. Functional properties and phenotypes of CD8⁺ T cells were assessed by IFN-? ELISPOT and 18 color flow cytometry. HIV controllers showed significantly increased suppression at baseline as well as after peptide stimulation. IFN-? secretion and the proliferation marker Ki67 positively correlated with VSC. Moreover, the detailed phenotype of three distinct multifunctional memory CD8⁺ T cell subsets were specific traits of HIV controllers of which two correlated convincingly with VSC. Our results underline the importance of multifunctional CD8⁺ T cell responses during natural control. Especially the role of CXCR5 expressing cytotoxic subsets emphasizes potential surveillance in sites of reservoir persistence and demand further study.

SUBMITTER: Adams P

PROVIDER: S-EPMC7945035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:Elite controllers, defined as persons maintaining undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, represent living evidence that sustained, natural control of HIV-1 is possible, at least in relatively rare instances. Understanding the complex immunologic and virologic characteristics of these specific patients holds promise for inducing drug-free control of HIV-1 in broader populations of HIV-1 infected patients. DESIGN:We used an unbiased transcriptional profiling approach to characterize CD8+ T cells, the strongest correlate of HIV-1 immune control identified thus far, in a large cohort of elite controllers (n?=?51); highly active antiretrovial therapy (HAART)-treated patients (n?=?32) and HIV-1 negative (n?=?10) served as reference cohorts. METHODS:We isolated mRNA from total CD8+ T cells isolated from peripheral blood mononuclear cell (PBMC) of each individual followed by microarray analysis of the transcriptional signatures. RESULTS:We observed profound transcriptional differences [590 transcripts, false discovery rate (FDR)-adjusted P?<?0.05] between elite controller and HAART-treated patients. Interestingly, metabolic and signalling pathways governed by mammalian target of rapamycin (mTOR) and eIF2, known for their key roles in regulating cellular growth, proliferation and metabolism, were among the top functions enriched in the differentially expressed genes, suggesting a therapeutically actionable target as a distinguishing feature of spontaneous HIV-1 immune control. A subsequent bootstrapping approach distinguished five different subgroups of elite controller, each characterized by distinct transcriptional signatures. However, despite this marked heterogeneity, differential regulation of mTOR and eIF2 signalling remained the dominant functional pathway in three of these elite controller subgroups. CONCLUSION:These studies suggest that mTOR and eIF2 signalling may play a remarkably universal role for regulating CD8 T-cell function from elite controllers.

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Cytotoxic CD8+ T Cells Expressing CXCR5 Are Detectable in HIV-1 Elite Controllers After Prolonged In Vitro Peptide Stimulation.

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