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T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable

Joglekar, Alok V. and Liu, Zhe and Weber, Jeffrey K. and Ouyang, Yong and Jeppson, John D. and Noh, Won Jun and Lamothe-Molina, Pedro A. and Chen, Huabiao and Kang, Seung-gu and Bethune, Michael T. and Zhou, Ruhong and Walker, Bruce D. and Baltimore, David (2018) T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable. Proceedings of the National Academy of Sciences of the United States of America, 115 (8). pp. 1877-1882. ISSN 0027-8424.

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HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2018 National Academy of Sciences. Published under the PNAS license. Contributed by David Baltimore, January 3, 2018 (sent for review November 2, 2017; reviewed by Mark Connors and Daniel C. Douek) published ahead of print February 7, 2018, We thank Caltech Office of Laboratory Animal Research staff for assistance with mouse models, members of the D.B. laboratory for their assistance and suggestions throughout the study, and Michael Leonard and Alexa Parker for their technical assistance. We thank David Gjertson for assistance with statistical analyses. This study was supported by an Innovation Award from Ragon Institute, Caltech Innovation Initiative award, California Institute of Regenerative Medicine Award DISC2-09123, and Leidos Biomedical Research, Inc. Subcontract 11XS287. Support for obtaining primary cells was also provided by NIH-funded Centers for AIDS Research (Grant P30 AI027763, UCLA Center for AIDS Research, and Grant P30 AI060354, Harvard University Center for AIDS Research, which are supported by the following NIH cofunding and participating institutes and centers: NIAID, National Cancer Institute, National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Aging, Fogarty International Center, and Office of AIDS Research). HCs were recruited with support from the Mark and Lisa Schwartz Foundation. Statement of Ethics and Regulations. PBMCs from HIV+ patients or healthy donors were collected according to protocols approved by Institutional Review Boards of Massachusetts General Hospital and California Institute of Technology. In vitro and in vivo studies were performed as per the regulations of the Caltech Institutional Biosafety Committees. All of the in vivo experiments were performed as per the regulations of the Caltech Institutional Animal Care and Use Committee. Author contributions: A.V.J., J.K.W., W.J.N., H.C., M.T.B., R.Z., B.D.W., and D.B. designed research; A.V.J., Z.L., J.K.W., Y.O., J.D.J., W.J.N., P.A.L.-M., H.C., S.-g.K., and M.T.B. performed research; A.V.J., J.K.W., P.A.L.-M., H.C., and B.D.W. contributed new reagents/analytic tools; A.V.J., Z.L., J.K.W., Y.O., J.D.J., W.J.N., P.A.L.-M., S.-g.K., M.T.B., R.Z., B.D.W., and D.B. analyzed data; and A.V.J., J.K.W., R.Z., B.D.W., and D.B. wrote the paper. This article contains supporting information online at The authors declare no conflict of interest. Reviewers: M.C., National Institute of Allergy and Infectious Diseases, National Institutes of Health; and D.C.D., National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Funding AgencyGrant Number
Ragon InstituteUNSPECIFIED
Caltech Innovation Initiative (CI2)UNSPECIFIED
California Institute for Regenerative Medicine (CIRM)DISC2-09123
Leidos Biomedical Research, Inc.11XS287
NIHP30 AI027763
NIHP30 AI060354
Mark and Lisa Schwartz FoundationUNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20180208-164208568
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Official Citation:TCRs for the HIV KK10 epitope. Alok V. Joglekar, Zhe Liu, Jeffrey K. Weber, Yong Ouyang, John D. Jeppson, Won Jun Noh, Pedro A. Lamothe-Molina, Huabiao Chen, Seung-gu Kang, Michael T. Bethune, Ruhong Zhou, Bruce D. Walker, David Baltimore. Proceedings of the National Academy of Sciences Feb 2018, 115 (8) 1877-1882; DOI: 10.1073/pnas.1718659115
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84752
Deposited By: George Porter
Deposited On:09 Feb 2018 23:52
Last Modified:03 Oct 2019 19:22

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