Vectored immunotherapy sustains long-term HIV suppression after antiretroviral therapy interruption 2257591

Abstract

Abstract Introduction HIV persists as a pandemic to this day, and although current antiretroviral therapies (ART) are effective, their success relies on strict adherence to the treatment. Broadly neutralizing antibodies (bNAbs) have also been evaluated as a therapeutic approach, but their implementation is undermined by the need for repeated infusions. We previously showed that vectored delivery of individual bNAbs via a single adeno-associated viral (AAV) vector injection results in long-lived expression of antibodies. This approach was effective as prophylaxis but usually failed to suppress actively replicating HIV in humanized mice. Recent reports in humans show that infusion of bNAbs during ART, followed by treatment interruption (ATI), results in viral suppression for as long as serum antibody concentrations remain high. Moreover, recent studies with SIV in the NHP model suggest that Vectored Immunotherapy (VIT) coupled with ART can improve therapeutic outcomes. Methods To evaluate whether this would also apply to HIV, humanized BLT mice were infected with different clinical isolates, and then ART-containing food was administered. Following viral suppression, AAVs encoding different bNAbs were administered individually or in combinations and then subjected to ATI. Results Administration of individual bNAbs during ART treatment followed by ATI resulted in significantly improved viral suppression, relative to mice treated with only AAV-bNAbs. However, antibody monotherapy was not sufficient to completely suppress all the HIV isolates tested. When double combinations of bNAbs were tested, the therapeutic success was further improved, achieving suppression of harder-to-neutralize isolates. Finally, when testing a combination of three antibodies replicating previous clinical trials, complete suppression was achieved for all tested isolates. Conclusion This finding suggests that vectored delivery of bNAbs via AAV is a potential therapeutic alternative to achieve a functional cure for HIV. Funding Source The National Institute for Allergy and Infectious Disease Career Transition Award K22AI102769, Research Grants R01AI174875, R01AI174276, the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the NIDA Avant-Garde Award 1DP1DA060607, CDC subcontract 200-2016-91773-T.O.2, the Executive Committee on Research (ECOR) of the Mass General Hospital (MGH) Fund for Medical Discovery, MGH Transformative Scholars Program, the Charles H. Hood Foundation, and the Gilead Sciences Research Scholars Program in HIV. Topic Categories Vaccines and Immunotherapy (VAC)