Harnessing the IL-15 Signaling Pathway for HIV Cure Approaches

The HIV-1 latent reservoir remains the largest barrier to cure, despite the development and progress of effective antiretroviral therapies. One of the most highly studied cure strategies under investigation is the “Shock and Kill” strategy. Latency reversing agents (LRAs) are used to transcriptionally activate latent virus (“Shock”), leading to subsequent clearing of infected cells either by immune effector cells or inherent viral cytopathicity (“Kill”). A variety of LRAs have been tested for efficacy in vivo, however none have shown the ability to significantly reduce the latently infected cell population thus far. IL-15 or the IL-15 superagonist N-803 have some promise as potential LRA in vitro and ex vivo but its in vivo efficacy is limited. To that end, the development of additional therapeutics that enhance IL-15 signaling are critical for the progression of effective HIV cure strategies when IL-15 is used. In this work, we first identified the targets of the LRA HODHBt as the non-receptor tyrosine phosphatases PTPN1 and PTPN2. These enzymes have previously been implicated in disease progression of type-I diabetes, and clinical obesity, and have also been highlighted as targets for cancer immunotherapy strategies. We have now highlighted them as promising HIV cure therapeutic targets in combination with IL-15 and begun to investigate more potent specific inhibitors as next generation LRAs. Next, we describe the FDA-approved compound Isotretinoin as an LRA. Isotretinoin enhances IL-15-mediated HIV latency reversal in a primary cell model, and also promotes HIV-infected cell death through increased caspase activation. Finally, we identify CD4/CD8 ratio as a positive correlate of IL-15 reactivation of translation-competent virus from people living with HIV (PWH). This result can have clinical implications when using IL-15 or the IL-15 superagonist N- 803 as an LRA. Together, the data described in this dissertation present two novel avenues for improvement of “Shock and Kill” HIV cure strategies when using IL-15- based strategies.

Author

• Howard, Jacqueline Natalie

Language

• en

Keyword

• JAK/STAT signaling
• HIV

Date created

• 2024

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Microbiology & Immunology

Degree

• Ph.D.

Advisor

• Bosque, Alberto

Committee Member(s)

• Chiappinelli, Katherine
• Bolton, Diane
• Lynch, Rebecca
• Chang, Aileen
• Leitenberg, David

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/8w32r6779