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Some Aspects of CD8+ T-Cell Exhaustion Are Associated With Altered T-Cell Mitochondrial Features and ROS Content in HIV Infection

Deguit, Christian Deo T. MSa,b; Hough, Michelle BAa,c; Hoh, Rebecca MS, RDa; Krone, Melissa MSd; Pilcher, Christopher D. MDa; Martin, Jeffrey N. MD, MPHd; Deeks, Steven G. MDa; McCune, Joseph M. MD, PhDa,e; Hunt, Peter W. MDa; Rutishauser, Rachel L. MD, PhDa

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2019 - Volume 82 - Issue 2 - p 211–219
doi: 10.1097/QAI.0000000000002121
Basic Science
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Background: Reversing or preventing T-cell exhaustion is an important treatment goal in the context of HIV disease; however, the mechanisms that regulate HIV-specific CD8+ T-cell exhaustion are incompletely understood. Since mitochondrial mass (MM), mitochondrial membrane potential (MMP), and cellular reactive oxygen species (ROS) content are altered in exhausted CD8+ T cells in other settings, we hypothesized that similar lesions may arise in HIV infection.

Methods: We sampled cryopreserved peripheral blood mononuclear cells from HIV-uninfected (n = 10) and HIV-infected participants with varying levels and mechanisms of viral control: viremic (VL > 2000 copies/mL; n = 8) or aviremic (VL < 40 copies/mL) due to antiretroviral therapy (n = 11) or natural control (n = 9). We characterized the MM, MMP, and ROS content of bulk CD8+ T cells and MHC class I tetramer+ HIV-specific CD8+ T cells by flow cytometry.

Results: We observed higher MM, MMP, and ROS content across bulk effector-memory CD8+ T-cell subsets in HIV-infected compared with HIV-uninfected participants. Among HIV-specific CD8+ T cells, these features did not vary by the extent or mechanism of viral control but were significantly altered in cells displaying characteristics associated with exhaustion (eg, high PD-1 expression, low CD127 expression, and impaired proliferative capacity).

Conclusions: While we did not find that control of HIV replication in vivo correlates with the CD8+ T-cell MM, MMP, or ROS content, we did find that some features of CD8+ T-cell exhaustion are associated with alterations in mitochondrial state. Our findings support further studies to probe the relationship between mitochondrial dynamics and CD8+ T-cell functionality in HIV infection.

aDepartment of Medicine, University of California, San Francisco, San Francisco, CA;

bCurrently, Department of Biochemistry and Molecular Biology, University of the Philippines, Manila, Philippines;

cCurrently, Department of Medicine, University of Southern California, Los Angeles, CA;

dDepartment of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA; and

eGlobal Health Discovery & Translational Sciences, Currently, Bill & Melinda Gates Foundation, Seattle, WA.

Correspondence to: Rachel L. Rutishauser, MD, PhD, Department of Medicine, University of California, San Francisco Division of Experimental Medicine, Zuckerberg San Francisco General Hospital, 1001 Potrero Avenue, Building 3, Room 603, San Francisco, CA 94110 (e-mail: Rachel.Rutishauser@ucsf.edu).

Supported by the National Institutes of Health (5R32AI060530 and K23AI1334327 [R.L.R.], 5K24AI069994 [S.G.D.], R01HD074511 [C.D.P.], AI110271 [P.W.H.], and UCSF/Gladstone Institute of Virology and Immunology CFAR: P30 AI027763), the Philippine Department of Science and Technology-Science Education Institute (C.D.T.D.), and a CFAR Mentored Scientist Award (R.L.R.). Additional support for SCOPE was provided by the Delaney AIDS Research Enterprise (DARE; AI096109) and the amfAR Institute for HIV Cure Research (amfAR 1093t01). Options cohort support was also provided by the Bill and Melinda Gates Foundation (OPP1062806) and the Harvey V. Berneking Living Trust.

Presented at the (as a poster) Conference on Retroviruses and Opportunistic Infections (CROI); March 7, 2018; Boston, MA.

The authors have conflicts of interest to disclose.

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Received February 11, 2019

Accepted May 14, 2019

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