Chimeric antigen receptor T-cell approaches to HIV cure

Abstract

Purpose of review: Combination antiretroviral therapy (ART) has enabled tremendous progress in suppressing HIV replication in infected patients. However, ART alone cannot eradicate HIV and its latent, persisting reservoirs. Novel approaches are needed to eradicate the virus or achieve functional cure in the absence of ART.

Recent findings: Adoptive T-cell therapies were initially tested in HIV-infected individuals with limited efficiency. Benefiting from new and improved methodologies, an increasing array of CAR T-cell therapies has been successfully developed in the cancer immunotherapy field, demonstrating promising new avenues that could be applied to HIV. Numerous studies have characterized various HIV-specific CAR constructs, types of cytolytic effector cells, and CAR-expressing cells' trafficking to the reservoir compartments, warranting further in-vivo efforts. Notably, the ability of CAR cells to persist and function in low-antigen environments in vivo, that is, in ART-suppressed patients, remains unclear.

Summary: Despite promising results in preclinical studies, only a handful of clinical trials have been initiated worldwide. Several obstacles remain prior to successful application of HIV-specific CAR T-cell therapies in patients. In this review, we survey the current state of the field, and address paths towards realizing the goal of an efficacious HIV CAR T-cell product.

Figure 1

Comparison of CD4ζ - and bNAb-based CARs, and modulation of CAR T cell activation and potency. CD4ζ -based CARs possess lower affinity (strength of the binding between epitope and binding site) but higher avidity (cumulative strength of an interaction, factoring in multiple epitopes/binding sites), potentially leading to more potent T cell activation relative to bNAb-based CARs. The proper combination of affinity, avidity, and accessibility of the targeted epitope(s), among other parameters, are likely key in determining CAR-T cell potency.