T Cell Receptor Immunotherapy Drives Human Immunodeficiency Virus Evolution in Humanized Mice

Creators: Joglekar, Alok V.; Swift, Margaret; Leonard, Michael T.; Jeppson, John D.; Sandoval, Salemiz; Baltimore, David

Abstract

Effective CD8+ T cell responses targeted to the KK10 epitope of HIV presented by HLA-B*27:05, a protective HLA allele, correlate with the ability to control infection without antiretroviral therapy (ART). Here, we report an immunotherapy approach using two B*27:05-KK10-specific T Cell Receptors (TCRs) isolated from HIV controllers. Immunocompromised mice engrafted with human Hematopoietic Stem/Progenitor Cells (HSPCs) encoding for the TCRs showed differentiation into functionally active engineered T cells. Following infection with HIV, both TCRs showed sustained, albeit modest, viral suppression over 32 weeks, accompanied by a concomitant increase in CD4+ T cells. Sequencing of viral quasi-species from the plasma of infected mice demonstrated clear evidence for viral evolution under selection pressure from the TCRs. The most commonly observed mutation in the KK10 epitope was L6M, which preserved viral fitness but showed attenuated recognition by the TCRs. These studies show that TCR-immunotherapy was able to suppress HIV infection long-term while driving HIV evolution in humanized mice.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv preprint first posted online Mar. 12, 2019. We thank the staff at Caltech's Office of Laboratory Animal Research, particularly John Papsys, Brittney Garcia, Gwen Williams, Ruben Bayon, and Dr. Karen Lencioni for their assistance with mouse colony maintenance, timed matings, and maintenance of animal health. We thank Caroline Ignacio and Gemma Caballero at the University of California, San Diego, Center for AIDS Research Translational Virology Core for running ddPCR measurement for viral load. We thank Deborah Anisman-Posner and Alex Bollinger at the University of California, Los Angeles, Center for AIDS Research Virology Core for collecting PBMCs from healthy donors and for running p24 measurement from viral supernatant. We thank the staff at the Fred Hutchinson Cancer Research Center Core in Experimental Hematology for screening HSPC donors and for collecting and enriching mPB-HSPCs from healthy donors. We thank Rishi Bhargava for assistance with generating pie charts depicting the frequencies of viral quasi-species. We thank Dr. Anjie Zhen, Dr. Scott Kitchen, and members of the Baltimore laboratory for discussions and suggestions regarding the study. We thank Zhe Liu and Won-Jun Noh for technical assistance. Finally, we thank Dr. Bruce D. Walker at the Ragon Institute for MGH, MIT, and Harvard for providing HIV controller samples from which the TCRs were isolated, as well as for scientific insights and discussions. This study was funded by the California Institute for Regenerative Medicine grant DISC2-09123 and California Institute of Technology Innovation Initiative. Conflict of Interest Disclosure: S.S. is an employee of Kite Pharma, a Gilead Company. All other authors declare no conflicts of interest. Author Contributions: A.V.J. conceptualized the study, obtained funding that led to the study, designed and performed experiments, analyzed the data, and wrote the manuscript. M.S. performed in vitro and in vivo experiments, analyzed the data, and wrote the manuscript. M.T.L. performed in vitro experiments and analyzed viral sequencing data. J.D.J. and S.S. performed experiments, D.B. conceptualized the study, obtained funding that led to the study, oversaw the study, and wrote the manuscript.

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