In recent years, MHRP's focus has expanded beyond advancing an effective HIV vaccine to include research into how to induce long term HIV remission. The program's "functional cure" studies seek to find an effective tool that will allow people living with HIV to be able to control the virus without the need for long term anti-retroviral treatment (ART). Interventions are wide-ranging and include therapeutic HIV vaccines and broadly neutralizing antibodies.
Treatment Interruption Remission Research
Drawing on the RV254 acute infection cohort, a subset of volunteers is asked to participate in early-phase trials that aim to generate knowledge relevant to an eventual functional cure of HIV. During these studies, volunteers are taken off ART to test the effects of a candidate intervention. This method, called analytical treatment interruption (ATI), looks at the time it takes for the viral load to rebound after the interruption. Participants are followed closely and restart ART when viral load rises to a certain threshold.
One of MHRP's first ATI studies decisively showed that, although initiating ART early in Fiebig stage I, before infection is even detectable with common diagnostic tests, improved a number of factors of HIV progression, early ART alone is not sufficient to delay viral rebound. Findings, published in Nature Medicine, suggest that future strategies should aim to eliminate cells with replication competent HIV in blood and tissues by boosting immune responses. Potential strategies include combination therapies with latency reversal or immune adjuvant agents, broadly neutralizing antibodies, ART intensification, therapeutic vaccines and/or cell-based or gene-based therapies.
Broadly Neutralizing Antibodies
MHRP's RV397 study evaluated a broadly neutralizing antibody (bNab) called VRC01 in a small intervention group in Thailand. VRC01, developed be the National Institutes of Health Vaccine Research Center, inhibits multiple strains of HIV by adhering to the CD4 binding site on the virus. The small Thai cohort trial showed that infusion of the bNAb in virally suppressed, early treated volunteers was associated with a modestly delayed rebound of HIV after interruption of ART. Results were published in The Lancet HIV.
The study was the first randomized controlled trial to demonstrate this effect of VRC01. One of the 13 participants who received VRC01 remained virally suppressed for 42 weeks post-treatment interruption. This study provides the basis for future studies in early treated people with combination bNAbs of higher potency. In addition, researchers will investigate the samples from this study to identify factors that might have contributed to the delay in rebound.
First Positive Signal in Therapeutic Vaccine Trial
MHRP and partners at the Thai Red Cross published results in Nature Medicine from a novel HIV clinical study, RV405, that examined the effects of a heterologous Ad26, MVA therapeutic vaccine regimen in a subset of participants from the Thai acute infection cohort. The vaccine was safe and generated robust immune responses, which tended to be associated with delayed time to viral rebound by several days compared to placebo recipients.
Though no single intervention has significantly delayed viral rebound after ART interruption, these small early phase trials are informing future potential functional cure strategies. Upcoming MHRP remission studies will aim to intervene earlier, at the time of diagnosis, and examine the effects of multiple interventions in combination. ATI studies have also provided valuable information for laboratory scientists seeking insights into correlates of viral rebound and biomarkers to help estimate reservoir size.
Social Behavioral Research
A central tenet of MHRP's work towards curing HIV is to conduct social and behavioral research in conjunction with treatment interruption studies. Social science and ethics research, led by collaborators Dr. Gail Henderson at the University of North Carolina School of Medicine and Dr. Holly Peay at RTI International, seeks to understand the decision-making process of SEARCH10/RV254 cohort members who agree and decline to participate in ATI studies.