Suppression of viral rebound by a Rev-dependent lentiviral particle in SIV-infected rhesus macaques

Existing antiretroviral therapy (ART) effectively suppresses viral replication but cannot eradicate HIV because of the persistence of viral reservoirs. When ART is stopped, these reservoirs cause viral rebound. The researchers tested a novel "rehab and redeem" strategy using a Rev-dependent lentiviral vector designed to selectively express therapeutic genes only in cells actively expressing the HIV/SIV Rev protein, effectively targeting the viral reservoir. The study used SIV-infected rhesus macaques to assess whether this vector could reduce viral rebound, with some animals also receiving ganciclovir (GCV) to trigger cell killing via an HSV-1 thymidine kinase (HSV-1-tk) gene incorporated into the vector.

The researchers found that injecting the Rev-dependent particles allowed the vector to mobilize and target reservoir cells in vivo. One particular macaque (KC50) treated with this regimen maintained undetectable plasma and CNS viral loads for over two years after ART cessation. Characterization of the immune response in KC50 revealed that the vector administration induced the production of potent, tier-2 neutralizing antibodies. The authors suggest that by partially targeting reservoir cells, the vector converts them into producers of non-infectious, immunogenic viral particles, which in turn stimulates the immune system to produce highly active antibodies capable of long-term viremia control.

Current strategies for HIV cure face the challenge of selectively targeting hidden viral reservoirs without damaging healthy cells. This study demonstrates a proof-of-concept for a therapeutic vector that requires only partial targeting of reservoirs to trigger a broader, more effective immune response. This approach potentially offers a way to achieve functional HIV remission without requiring the complete elimination of every infected cell in the body.