Interrogating Strategies to Enhance Cell-Based Therapies for the Treatment of HIV and HIV-Associated Cancers
Open AccessThe advent of antiretroviral therapy has led to the durable suppression of HIV replication in individuals living with HIV, however this approach is not curative. Reactivation of the persistent HIV reservoir is a risk to patients post hematopoietic stem cell transplantation (HSCT) and individuals with viral co-infections, such as Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of HIV-associated cancers. While there are five known cases of HIV+ patients with hematological malignancies that show undetectable HIV post allogeneic HSCT, this approach is high risk and not broadly applicable to people living with HIV. Current approaches for an HIV cure also include exploration of chimeric antigen receptor (CAR) T cell therapies, conferring resistance to HIV through gene editing approaches and/or HSCT, and induction of broadly neutralizing antibodies (bnAbs). However, these approaches have failed to prevent viral rebound, induce bnAbs, and are susceptible to viral immune escape mutations that thwart antiviral responses. Further, such strategies do not reduce the HIV reservoir. This body of work builds on an HIV-specific T cell therapy platform to demonstrate increases in anti-HIV T cell immunity specifically against conserved regions of HIV Gag and Pol, and the entire library of Nef peptides, termed HST-NEET products, to overcome immune escape mechanisms of epitope loss. In this thesis, I show that the administration of HST-NEET products recognizing HIV Gag, Pol, and Nef resulted in expansion and persistence of HIV-reactive T cells post infusion. Moreover, post infusion increases in HIV-specific T cell responses were observed and were associated with decreases in the HIV reservoir for some participants. Further, to broaden the applicability of this virus-specific T cell platform, I expanded the approach to expand KSHV-specific T cells that recognized novel KSHV oncoproteins from seronegative donors as an “off the shelf” therapeutic. I also show proof-of-concept studies that support the development of a CRISPR-Cas9 mediated gene-edited virus-specific T cell platform that may confer resistance to enveloped viruses like HIV and KSHV by targeting viral envelope glycoproteins critical for cell entry. Overall, discoveries revealed in this work have improved our understanding of novel cell-based therapies for the treatment of HIV and HIV-associated cancers.
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