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Susceptibility to CD8 T-Cell–Mediated Killing Influences the Reservoir of Latently HIV-1–Infected CD4 T Cells

Buzon, Maria J. PhD*,†; Yang, Yue MD*,†; Ouyang, Zhengyu PhD; Sun, Hong MD†,‡; Seiss, Katherine BSc; Rogich, Jerome BSc; Le Gall, Sylvie PhD; Pereyra, Florencia MD†,§; Rosenberg, Eric S. MD*; Yu, Xu G. MD; Lichterfeld, Mathias MD, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1st, 2014 - Volume 65 - Issue 1 - p 1–9
doi: 10.1097/QAI.0b013e3182a1bc81
Basic and Translational Science

Background: HIV-1 establishes a lifelong infection in the human body, but host factors that influence viral persistence remain poorly understood. Cell-intrinsic characteristics of CD4 T cells, the main target cells for HIV-1, may affect the composition of the latent viral reservoir by altering the susceptibility to CD8 T-cell–mediated killing.

Results: We observed that susceptibilities of CD4 T cells to CD8 T-cell–mediated killing, as determined in direct ex vivo assays, were significantly higher in persons with natural control of HIV-1 (elite controllers) than in individuals effectively treated with antiretroviral therapy. These differences were most pronounced in naive and in terminally differentiated CD4 T cells and corresponded to a reduced viral reservoir size in elite controllers. Interestingly, the highest susceptibility to CD8 T-cell–mediated killing and lowest reservoirs of cell-associated HIV-1 DNA was consistently observed in elite controllers expressing the protective HLA class I allele B57.

Conclusions: These data suggest that the functional responsiveness of host CD4 T cells to cytotoxic effects of HIV-1–specific CD8 T cells can contribute to shaping the structure and composition of the latently infected CD4 T-cell pool.

*Infectious Disease Division, Massachusetts General Hospital, Boston, MA;

Ragon Institute of MGH, MIT, and Harvard, Boston, MA;

Laboratory of AIDS Immunology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China; and

§Infectious Disease Division, Brigham and Women's Hospital, Boston, MA.

Correspondence to: Mathias Lichterfeld, MD, PhD, Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114 (e-mail:

The authors have no conflicts of interest to disclose. M.J.B. is supported by a fellowship award from the European Molecular Biology Organization. M.L. is supported by the US National Institutes of Health (AI093203, AI098487), by the Clinical Scientist Development Award from the Doris Duke Charitable Foundation (grant number 2009034), and by the American Foundation for AIDS Research (grant 108302-51-RGRL). Recruitment of HIV-1 controllers was supported by the Bill and Melinda Gates Foundation, the Mark and Lisa Schwartz Foundation, and the International HIV Controller Study.

Received March 29, 2013

Accepted June 21, 2013

© 2014 by Lippincott Williams & Wilkins