T-cell therapies for HIV: Preclinical successes and current clinical strategies

Abstract

Although antiretroviral therapy (ART) has been successful in controlling HIV infection, it does not provide a permanent cure, requires lifelong treatment, and HIV-positive individuals are left with social concerns such as stigma. The recent application of T cells to treat cancer and viral reactivations post-transplant offers a potential strategy to control HIV infection. It is known that naturally occurring HIV-specific T cells can inhibit HIV initially, but this response is not sustained in the majority of people living with HIV. Genetically modifying T cells to target HIV, resist infection, and persist in the immunosuppressive environment found in chronically infected HIV-positive individuals might provide a therapeutic solution for HIV. This review focuses on successful preclinical studies and current clinical strategies using T-cell therapy to control HIV infection and mediate a functional cure solution.

Keywords: CRISPR; HDACIs; HIV; ZFN; adoptive T-cell therapy; artificial TCR; chimeric antigen receptors; gene editing.

Figure 1. Redirecting HIV-Specific Immune Responses

This figure highlights three main strategies to redirect HIV-specific immune responses. First, stimulating and expanding T cells ex vivo against HIV antigens, such as nef, gag, and pol, to generate multi-antigen HIV-specific T cells that can control HIV replication (top). Second, transducing T cells with a viral vector to express a CAR or artificial TCR on the cell surface that can target specific HIV epitopes, such as those epitopes important for viral fitness (bottom).

Figure 2. Strategies to Improve Persistence and Function of Infused T Cells

HIV coreceptors CCR5 and CXCR4 are knocked out on CD4+ T cells using gene editing approaches such as ZFN and CRISPR, to provide HIV resistance. Memory T cells are enriched ex vivo using cell surface markers CD45RA/RO and CD62L to improve persistence of infused T cells.