Evolving Strategies to Eliminate the CD4 T Cells HIV Viral Reservoir via CAR T Cell Immunotherapy

Abstract

Although the advent of ART has significantly reduced the morbidity and mortality associated with HIV infection, the stable pool of HIV in latently infected cells requires lifelong treatment adherence, with the cessation of ART resulting in rapid reactivation of the virus and productive HIV infection. Therefore, these few cells containing replication-competent HIV, known as the latent HIV reservoir, act as the main barrier to immune clearance and HIV cure. While several strategies involving HIV silencing or its reactivation in latently infected cells for elimination by immune responses have been explored, exciting cell based immune therapies involving genetically engineered T cells expressing synthetic chimeric receptors (CAR T cells) are highly appealing and promising. CAR T cells, in contrast to endogenous cytotoxic T cells, can function independently of MHC to target HIV-infected cells, are efficacious and have demonstrated acceptable safety profiles and long-term persistence in peripheral blood. In this review, we present a comprehensive picture of the current efforts to target the HIV latent reservoir, with a focus on CAR T cell therapies. We highlight the current challenges and advances in this field, while discussing the importance of novel CAR designs in the efforts to find a HIV cure.

Development of an anti-CAR antibody response in SIV-infected rhesus macaques treated with CD4-MBL CAR/CXCR5 T cells

“…Some CAR T cell studies have reported persistence, and functional persistence of CAR T cells in vivo for more than 10 years in humans ( 24 , 25 ) and 2 years in rhesus macaques ( 24 – 26 ). However, in general, persistence remains a challenge for CAR T cell therapy, especially as a treatment for HIV ( 27 , 28 ).…”

Opportunities for CAR-T Cell Immunotherapy in HIV Cure

“…To address this drawback, in place of CD4 as the extracellular antigen recognition domain, broadly neutralizing antibodies (bNAbs) against HIV are engineered in the CAR construct. Approximately 1–2% of HIV-infected individuals generate these antibodies [ 48 ], which present a high affinity for the HIV envelope protein. In recent years, many bNAbs have been isolated that target different epitopes of the gp160 protein [ 49 ].…”

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

“…The receptor that recognizes and binds to the virus is determined by the virus. For example, in the influenza virus, the structure of sialic acid sugar chains on the surface of upper and lower respiratory tract cells functions as a viral receptor [ 38 ], and in HIV, a protein called CD4 on immune cells functions as a viral receptor [ 39 ]. ACE2 is involved in the breakdown of a blood pressure-regulating autocoid called angiotensin II; however, the infection does not cause sudden changes in blood pressure.…”