Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
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DOI：
10.3389/fimmu.2022.908697
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
CD 8 T细胞耗竭是HIV-1感染的一个标志，其特征是尽管多年有效的抗逆转录病毒治疗（ART），但仍持续存在表型和功能性CD 8 T细胞异常。最近，细胞代谢在塑造T细胞抗病毒功能中的重要性已经成为旨在重新激活耗尽的CD 8 T细胞的免疫治疗的一个关键方面，但在HIV-1感染中仍然研究不足。为了更好地了解这一过程并确定有效CD 8 T细胞恢复的新靶点，我们检查了HIV-1感染中耗尽的CD 8 T细胞的代谢谱。我们发现，相对于HIV-1精英控制者（EC）和HIV-1血清阴性供体，来自HIV-1病毒血症个体的CD 8 T细胞偏向于在ART期间维持的PD-1hiEOMEShiT-betlowTIGIT+表型。与CMV特异性CD 8 T细胞群体相比，这种耗尽的特征在HIV特异性CD 8 T细胞中富集，并进一步通过葡萄糖转运蛋白Glut-1，线粒体功能和生物发生受损，反映了潜在的代谢缺陷。通过线粒体抗氧化剂治疗结合线粒体动力学的药理学调节和IL-15治疗，引起抗病毒HIV特异性CD 8 T细胞功能的显著改善。这些发现将线粒体确定为HIV-1感染中联合重建疗法的有希望的靶点。
CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1hiEOMEShiT-betlowTIGIT+ phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited via mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.
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记忆CD8（+）T细胞使用细胞中性脂解来支持开发所需的代谢编程。
影响因子：
32.4
作者：
O'Sullivan, David;van der Windt, Gerritje J. W.;Huang, Stanley Ching-Cheng;Curtis, Jonathan D.;Chang, Chih-Hao;Buck, Michael D.;Qiu, Jing;Smith, Amber M.;Lam, Wing Y.;DiPlato, Lisa M.;Hsu, Fong-Fu;Birnbaum, Morris J.;Pearce, Edward J.;Pearce, Erika L.
通讯作者：
Pearce, Erika L.
影响因子：
16.6
作者：
Hurst J;Hoffmann M;Pace M;Williams JP;Thornhill J;Hamlyn E;Meyerowitz J;Willberg C;Koelsch KK;Robinson N;Brown H;Fisher M;Kinloch S;Cooper DA;Schechter M;Tambussi G;Fidler S;Babiker A;Weber J;Kelleher AD;Phillips RE;Frater J
通讯作者：
Frater J
影响因子：
6.7
作者：
Buggert M;Tauriainen J;Yamamoto T;Frederiksen J;Ivarsson MA;Michaëlsson J;Lund O;Hejdeman B;Jansson M;Sönnerborg A;Koup RA;Betts MR;Karlsson AC
通讯作者：
Karlsson AC
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1097/qad.0000000000000049
发表时间：
2014-01-14
期刊：
AIDS (London, England)
影响因子：
--
作者：
Gurdasani D;Iles L;Dillon DG;Young EH;Olson AD;Naranbhai V;Fidler S;Gkrania-Klotsas E;Post FA;Kellam P;Porter K;Sandhu MS
通讯作者：
Sandhu MS