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Hematopoietic stem/progenitor cells engineered with T cell receptors for immunotherapy for HIV infection

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.

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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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URLURL TypeDescription
Joglekar, Alok0000-0001-7554-7447
Leonard, Michael Troy0000-0001-9084-2647
Baltimore, David0000-0001-8723-8190
Additional Information:© 2018 by The American Association of Immunologists, Inc.
Issue or Number:S1
Record Number:CaltechAUTHORS:20190314-124617363
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93807
Deposited By: Tony Diaz
Deposited On:14 Mar 2019 19:54
Last Modified:09 Mar 2020 13:19

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