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• W2899863611 abstract "The study of protective immunity in HIV-1-infected individuals who naturally control virus replication can provide a roadmap for the induction of protective anti-HIV immunity. Elite controllers are a rare subset of HIV-1-infected individuals with an exquisite natural ability to control virus replication in the absence of therapy. A number of factors such as host genetics, virus fitness, intrinsic antiviral factors, host innate and adaptive immune responses are associated with virus control in elite controllers [1–7]. Among these factors are CD8+ T-cell responses known to be critical for the control of viremia in acute infection, the observed low virus load set point, delayed AIDS progression [7–12], and control of virus replication postvaccination in nonhuman primates [13,14]. A critical goal in the HIV/AIDS field is to define specific features of CD8+ T cells responsible for immunologic control that can be targeted by therapeutic interventions and/or vaccine strategies. Several studies have highlighted CD8+ T-cell features associated with virus control. These features include memory phenotype status [14–20], polyfunctionality [21–26], MIP-1β expression [20,27–29] proliferative capacity [30–33], pro-survival phenotype [34], functional avidity [22,35,36] and cross-reactivity [37]. Recent studies in rhesus macaques and humans also highlight unconventional CD8+ T cells (MHC class II-restricted and E-restricted CD8+ T cells) [14,38,39] and CD8+ T cells targeting highly conserved subdominant epitopes [40,41] as other potential CD8+ T-cell correlates of immunologic control. Advances in the field of immunometabolism reveal that an adequate nutrient supply and energy production are key determinants of the capacity of T cells to proliferate and mediate effector function [42]. Antigen-specific CD8+ T cells undergo energy-demanding processes, which include activation, clonal expansion, acquisition of effector functions, and persistence of memory T cells, that result in metabolic pathway reprograming [43,44]. Thus, differences in metabolic reprogramming can shape the efficacy of effector CD8+ T cells in response to natural infection. The importance of T-cell metabolism is highlighted by the fact that anergic and exhausted T cells in chronic viral infection downregulate genes involved in energy metabolism [45]. Ligation of inhibitory co-receptors that are up-regulated on dysfunctional tumor infiltrating lymphocytes and CD8+ T cells in chronic infection inhibits the upregulation of glucose and glutamine metabolism [46,47]. The potential role of metabolic state as a key determinant of CD8+ T-cell antiviral efficacy is highlighted by Trautmann et al.[48] who reported that HIV-1-specific CD8+ T cells in acute and chronic infection can be distinguished by their metabolic state with significant changes in the mechanistic targets of rapamycin (mTOR) signaling and protein ubiquitination pathways. CD8+ T cells in acute infection had a distinct metabolic state compatible with high levels of activation and proliferation [48]. mTOR signaling is utilized by T cells to integrate immune signals and metabolic cues for their proper maintenance and activation [49]. Activation of the mTOR signaling pathway is involved in CD8+ T-cell activation and generation of effector CD8+ T cells [50,51], whereas inhibition of mTOR signaling promotes the effector to memory CD8+ T-cell transition [50,52,53]. These findings further indicate the intersection of metabolic pathways and the fate of antigen-specific CD8+ T cells. The recent findings from Chowdhury et al.[54] in this issue of AIDS support the importance of CD8+ T-cell metabolic signaling pathways on cellular effector function in HIV infection. Chowdhury et al.[54] report that bulk peripheral CD8+ T cells from different HIV-1 patient cohorts can be stratified based on their metabolic state. Utilizing transcriptional profiling of CD8+ T cells from elite controllers, HAART-treated patients and HIV-1-negative donors, a unique transcriptomic signature involving metabolic and signaling pathways governed by mTOR and elF2 genes was identified. mTOR is a known key regulator of T-cell metabolism that is responsible for integrating signaling pathways associated with nutrient levels, energy status, cell stress responses, growth factor signaling, T-cell receptor signaling, T-cell differentiation and immune function [55–58]. Chowdhury et al.[54] also report that there is marked heterogeneity in the elite controller CD8+ T-cell transcriptome signature with the presence of five CD8+ T-cell subgroups with distinct transcriptional signatures. mTOR and eIF2-related genes were highly expressed in three of the five elite controller CD8+ T-cell groups. Heterogeneity among HIV-1 elite controllers was previously reported in that not all elite controllers rely on CD8+ T-cell activity for virus control [59], consistent with the different CD8+ T-cell clusters observed by Chowdhury et al. There are some outstanding questions to the Chowdhury et al.[54] report that include the possible influence of sex, race/ethnicity, HAART and protective HLA alleles on the observed differences between elite controllers and HAART-treated patients for mTOR and elF2-signaling pathways. Further work to examine CD8+ T-cell cytotoxic and antiviral functions will confirm whether modulation of mTOR and elF2-related gene expression observed in elite controllers translates to superior functional activity resulting in virus replication control. In summary, the Chowdhury et al.[54] study suggests that the different metabolic program of elite controller CD8+ T cells might be involved in their enhanced functional capacity and that this could be another qualitative feature associated with immunologic control. The fact that exhausted, dysfunctional CD8+ T cells also appear to have altered metabolic programs highlights the importance of cell metabolism in effector T-cell populations and the validity of T-cell metabolism as a potential therapeutic target. There are now therapeutic approaches aimed at targeting T-cell metabolism pathways as a way of enhancing their biological function [44,60]. Success by these approaches may further shape therapeutic and vaccine approaches in the HIV/AIDS field toward improving metabolic functions for optimal CD8+ T-cell responses. Acknowledgements We acknowledge support from the National Institutes of Health (NIH): National Institute of Allergy and Infectious Disease (NIAID), Duke Center for AIDS Research (P30 AI064518). Conflicts of interest There are no conflicts of interest." @default.
• W2899863611 created "2018-11-16" @default.
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• W2899863611 date "2018-11-28" @default.
• W2899863611 modified "2023-09-25" @default.
• W2899863611 title "CD8+ T cells" @default.
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• W2899863611 doi "https://doi.org/10.1097/qad.0000000000002008" @default.
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