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High Number of Activated CD8+ T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection

Kessing, Cari F. PhD*,†; Spudich, Serena MD; Valcour, Victor MD, PhD§; Cartwright, Pearline MSc*,†; Chalermchai, Thep MD; Fletcher, James L. K. BM, BCH; Takata, Hiroshi PhD¶,#; Nichols, Carmen PhD*,†; Josey, Benjamin J. PhD*,†; Slike, Bonnie MSc¶,#; Krebs, Shelly J. PhD¶,#; Sailsuta, Napapon PhD**; Lerdlum, Sukalaya MD††; Jagodzinski, Linda PhD; Tipsuk, Somporn BNS; Suttichom, Duanghathai MNS; Rattanamanee, Somprartthana MSc; Zetterberg, Henrik MD, PhD‡‡,§§; Hellmuth, Joanna MD, MHS§; Phanuphak, Nittaya MD, PhD; Robb, Merlin L. MD¶,#; Michael, Nelson L. MD, PhD#; Ananworanich, Jintanat MD, PhD‖,¶,#; Trautmann, Lydie PhD¶,#

JAIDS Journal of Acquired Immune Deficiency Syndromes: 01 May 2017 - Volume 75 - Issue 1 - p 108–117
doi: 10.1097/QAI.0000000000001301
Basic Science

Background: Central nervous system (CNS) infiltration by CD8+ T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8+ T cells in the CNS during acute HIV infection (AHI) is unknown.

Methods: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8+ T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8).

Results: CSF CD8+ T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8+ T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8+ T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8+ T cells in AHI exhibited increased functional gene expression profiles associated with CD8+ T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8+ T cells directed to unique HIV epitopes compared with the periphery.

Conclusions: These results suggest that CSF CD8+ T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.

*Vaccine and Gene Therapy Institute-Florida, Port St Lucie, FL;

Currently, Cari F. Kessing, Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL; Pearline Cartwright, Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH; Carmen Nichols and Benjamin J. Josey, Cell Therapies Institute, Nova Southeastern University, FL;

Yale University School of Medicine, New Haven, CT;

§Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA;

SEARCH, The Thai Red Cross AIDS Research Center, Bangkok, Thailand;

Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD;

#U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD;

**University of Hawaii, Honolulu, HI;

††Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;

‡‡Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; and

§§University College London Institute of Neurology, Queen Square, London, United Kingdom.

Correspondence to: Lydie Trautmann, PhD, Cellular Immunology Section, U.S. Military HIV Research Program, Henry M. Jackson Foundation, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910 (e-mail: ltrautmann@hivresearch.org).

Supported by the National Institutes of Health Grants (R01AI10843) (L.T.), (R01MH106466) (L.T.), (R21MH086341) (V.V.), (R01MH095613) (V.V. and S.S.), and a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense (DoD). Thai Pharmaceutical Organization, Merck, ViiV Healthcare and Gilead.

Presented as a poster at the Keystone Symposium, Boston, MA, April 27, 2015 and as an oral report at the International NeuroHIV Cure Consortium, January 15, 2015, Silver Springs, MD.

V.V. has served as a consultant for ViiV Healthcare and Merck, each of whom provide support for medications to these participants. S.S. has received travel support and an honorarium from AbbVie. J.A. has received honorarium from ViiV Healthcare, Merck and TetraLogic. The remaining authors have no conflicts of interest to disclose.

The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense.

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Received October 19, 2016

Accepted January 11, 2017

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