Joglekar, Alok and Sandoval, Salemiz and Jeppson, John and Liu, Zhe and Leonard, Michael Troy and Swift, Margaret and Baltimore, David (2018) Hematopoietic stem/progenitor cells engineered with T cell receptors for immunotherapy for HIV infection. Journal of Immunology, 200 (S1). Art. No. 180.5. ISSN 0022-1767. https://resolver.caltech.edu/CaltechAUTHORS:20190314-124617363
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Abstract
HIV infection causes progressive depletion of CD4+ T cells and leads to severe immunodeficiency if left untreated. Current antiretroviral therapy can control infection, but does not cure it. The goal of this study was to develop a “functional cure” for HIV infection by providing a long-term, self-renewing source of antiviral immunity. To that end, we hypothesized that immunotherapy using engineered hematopoietic stem/progenitor cells (HSPCs) to express HIV-specific T cell receptors (TCRs) will be effective at controlling HIV. We first isolated six TCRs specific to the KK10 epitope from HLA-B27+ individuals and compared their function in vitro. Two TCRs, EC27 and EC5.5, were chosen for immunotherapy studies based on their superior function. To test HSPC-based immunotherapy, we transduced mobilized peripheral blood CD34+ HSPCs from HLA-B27+ healthy donors to express these TCRs and engrafted them in immunocompromised NOD/SCID/IL2Rγc−/− (NSG) mice. Transduced HSPCs were able to engraft mice and differentiate into T cells expressing the TCRs in peripheral blood and lymphoid tissues. Furthermore, engineered T cells isolated from engrafted mice showed KK10-driven expansion, cytotoxicity, and cytokine secretion. Expanded T cells were able to inhibit HIV-infection in vitro. Moreover, the functional activity of engineered T cells isolated from mice was comparable to modified primary T cells, highlighting their therapeutic potential. We are currently testing whether mice engrafted with transduced HSPCs can suppress HIV infection in vivo. If successful, these studies would demonstrate a “functional cure” of HIV infection, warranting further testing in clinical trials.
Item Type: | Article | ||||||||
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Additional Information: | © 2018 by The American Association of Immunologists, Inc. | ||||||||
Issue or Number: | S1 | ||||||||
Record Number: | CaltechAUTHORS:20190314-124617363 | ||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20190314-124617363 | ||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||
ID Code: | 93807 | ||||||||
Collection: | CaltechAUTHORS | ||||||||
Deposited By: | Tony Diaz | ||||||||
Deposited On: | 14 Mar 2019 19:54 | ||||||||
Last Modified: | 09 Mar 2020 13:19 |
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