Advancements in Cell-Based Therapies for HIV Cure

Abstract

The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure. Here, we offer a consolidated overview of cell-based therapies for HIV-1, focusing on CAR-T cell approaches, gene editing, and immune modulation. Persistent challenges, including CAR-T cell susceptibility to HIV infection, stability, and viral reservoir control, underscore the need for continued research. This review synthesizes current knowledge, highlighting the potential of cellular therapies to address persistent challenges in the pursuit of an HIV cure.

Keywords: AIDS; Berlin Patient; CAR-T cell; CCR5; CD34+ cell; CD4+ T cell; CRISPR/Cas9; HIV-1; clinical trials; combination ART; cure study; cytokine release syndrome; cytotoxic T lymphocyte; elite controller; functional cure; latency; latency-reversing agents; off-the-shelf.

Figure 1

(A) Schematic of the structure of a chimeric antigen receptor (CAR) [33,34,35]. The first generation incorporates the CD3ζ chain as the intracellular signaling component. In the second generation, additional co-stimulatory molecules, such as CD28 [36] and 4-1BB [37], are introduced. The third generation is characterized by the presence of two co-stimulatory molecules aimed at enhancing cytotoxicity and promoting long-term viability. In the fourth generation [33,40], an intracellular interleukin domain, IL-12, is integrated, leading to the release of IL-12 upon CAR expression. The fifth generation introduces a cleavage domain of IL2Rβ and a STAT3-binding motif to the intracellular domains of CD28 and CD3ζ, further augmenting proliferation and ensuring prolonged viability. (B) Research on CAR-T cells for HIV-1 infection [41,42,43,44,45,46,47]. One approach to prevent the infection of CAR-T cells themselves involves modifying the extracellular domain of the CAR, shifting from CD4 to broadly neutralizing antibodies (bNAb) [45]. Another is the genetic modification of C-C-chemokine receptor-5 (CCR5) to enhance resistance. Additionally, efforts are underway to employ an extracellular domain capable of recognizing multiple epitopes, serving as a countermeasure against HIV immune evasion [46]. Studies highlighted in boldface type denote clinical investigations. TM, transmembrane; scFv, single-chain variable fragments.

Figure 2

Two cellular therapeutic strategies against HIV-1. CD8⁺ CAR-T cells aim to directly reinstate cytotoxic functionality against HIV-1-infected cells by providing supplementary cytotoxic T lymphocytes (CTLs). Conversely, the strategy involving CCR5-modified CD4⁺ T cells focuses on activating HIV-1-specific immunity through the introduction of infection-resistant T cells. Based on the outcomes of prior studies, these two strategies appear both promising and complementary. Further investigation, including exploration of combination therapy, is warranted to optimize their potential efficacy.