Conditionally Replicating Vectors Mobilize Chimeric Antigen Receptors against HIV

Area of Science:

• Immunology
• Virology
• Gene Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows potential for targeting Human Immunodeficiency Virus (HIV).
• HIV envelope glycoprotein (gp120) is a key target for CAR T-cell-mediated eradication.
• HIV reactivation from infected cells poses a challenge for CAR T-cell therapy.

Purpose of the Study:

• To evaluate the efficacy of CAR T-cells utilizing different single-chain variable fragments (scFvs) against HIV-infected cells.
• To develop and assess a conditionally replicating lentiviral vector (crLV) for enhancing CAR T-cell therapy in HIV patients.
• To investigate the potential of crLV-generated CAR T-cells to overcome HIV reactivation in CD4+ T-cells.

Main Methods:

• Screening of neutralizing scFvs targeting HIV gp120 to identify potent CAR T-cell constructs.
• Development of a crLV designed to hijack HIV machinery for CAR T-cell generation.
• Assessment of CAR T-cell cytotoxicity against antigen-expressing cells.
• Evaluation of crLV-mediated CAR T-cell expansion and CD4+ T-cell protection in HIV donors.

Main Results:

• CAR T-cells engineered with the NIH45-46 scFv demonstrated superior cytotoxicity against HIV-infected cells.
• crLVs were successfully developed and generated CAR T-cells with comparable functionality to traditional CARs.
• crLVs effectively increased CAR expression and protected CD4+ T-cells in HIV patient samples, mitigating reactivation issues.

Conclusions:

• The NIH45-46 CAR T-cell strategy shows significant potential for combating HIV by targeting infected cells.
• Novel crLVs offer a promising approach to enhance CAR T-cell therapy for HIV, improving CAR percentage and CD4+ T-cell survival.
• This combined strategy presents a viable therapeutic option to address HIV infection and manage viral reactivation in patients.