Engineering T Cells to Functionally Cure HIV-1 Infection

Abstract

Despite the ability of antiretroviral therapy to minimize human immunodeficiency virus type 1 (HIV-1) replication and increase the duration and quality of patients' lives, the health consequences and financial burden associated with the lifelong treatment regimen render a permanent cure highly attractive. Although T cells play an important role in controlling virus replication, they are themselves targets of HIV-mediated destruction. Direct genetic manipulation of T cells for adoptive cellular therapies could facilitate a functional cure by generating HIV-1-resistant cells, redirecting HIV-1-specific immune responses, or a combination of the two strategies. In contrast to a vaccine approach, which relies on the production and priming of HIV-1-specific lymphocytes within a patient's own body, adoptive T-cell therapy provides an opportunity to customize the therapeutic T cells prior to administration. However, at present, it is unclear how to best engineer T cells so that sustained control over HIV-1 replication can be achieved in the absence of antiretrovirals. This review focuses on T-cell gene-engineering and gene-editing strategies that have been performed in efforts to inhibit HIV-1 replication and highlights the requirements for a successful gene therapy-mediated functional cure.

Figure 1

Summary of gene-engineering and gene-editing strategies to functionally cure HIV-1 infection. A variety of antiviral proteins and antiviral RNAs have been intracellularly expressed in CD4 T cells to interfere with virus propagation early or late in the virus lifecycle, upon entry or in the nuclear or cytoplasmic stages of virus replication and virion assembly. Designer nucleases have been employed to disrupt expression of integrated proviruses and to generate HIV-resistant cells by knocking out the coreceptors required for virus entry. CD8 and CD4 T cells can be redirected to kill infected cells with HIV-specific TCRs and CARs. Immune-mediated control over HIV in the absence of HAART will likely require the protection of key CD4 T-cell helper subsets from HIV infection so that HIV-specific activation will result in effector functions including IL-2 and IL-21 production and expression of CD40 ligand.