Team demonstrates unprecedented control of SIV replication using immune-based approach

Emory researchers are the first to demonstrate unprecedented control of SIV replication and viral reservoir degradation by combining a rigorous infection model with antiretroviral therapy (ART) interruption. The success of this immune-based approach follows the research team’s identification of the mechanisms of action of PD1 and IL-10, molecules known to regulate HIV persistence and immune dysfunction.

The results of the study are reported in Natural immunology.

“This is a major step forward in the fight to achieve a cure for HIV that will improve the lives of the 39 million people living with the disease,” said Rafick Sekaly, Ph.D., principal investigator of the study and co-director of the Martin Delaney Collaboratory for HIV Cure Research, “Reversing Immune Dysfunction for HIV-1 Eradication” (the RID HIV Collaboratory).

“Our work on PD1 and IL-10, which began more than 15 years ago, has led us to develop this in vivo intervention in non-human primates (NHPs). This better understanding of PD1 and IL-10 will allow our team to develop improved approaches to restore a deficient immune system, strengthen immune interventions to improve the control of chronic infections and even offer hope for better treatment of certain cancers,” he continues.

The NHP arm of this study, which included 28 SIV-infected rhesus macaques treated with ART, a highly characterized animal model for SIV infection, was critical to better understanding PD1 and IL-10. Mirko Paiardini, Ph.D., and Zachary Strongin led the research to develop the rigorous model of HIV/SIV infection, ART treatment, and anti-IL-10 immune intervention, a combination of anti-IL-10 plus anti-PD-1 or placebo.

After 14 months of antiretroviral treatment, the researchers began treating the animals with immunotherapy. Twelve weeks later, the researchers continued immunotherapy but stopped antiretroviral treatment. Nine of the 10 monkeys that received the combination treatment showed sustained control of viral rebound that lasted for six months.

Paiardini is also co-director and principal investigator for a Martin Delaney Collaboratory, the Enterprise for Research and Advocacy to Stop and Eradicate HIV (the ERASE HIV Collaboratory).

Strongin is a senior immunology scientist at Merck and a former graduate student in the Paiardini lab. Merck, an industrial partner in the RID HIV and ERASE HIV collaborations, has developed reagents specifically designed to target PD1 and IL10 molecules in non-human primate models.

Sekaly credits the research collaboration between academia and industry, as well as the expertise of each team member, as the cornerstones of this study. “The scientific collaboration between RID HIV, ERASE HIV and Merck colleagues that led to the unparalleled results of this study exemplifies the goal of the Martin Delaney Collaboratories: to accelerate HIV treatment research by bringing together researchers to share resources, data and methodologies.”

First author Susan Ribeiro, Ph.D., and her bioinformatics team, including Khader Ghneim, MS, and Felipe ten Caten, Ph.D., used their methodological expertise to develop a unique systems biology platform that allowed the research team to exploit all facets and cells of the immune response.

This comprehensive approach facilitated the team’s identification of novel immune mechanisms underlying the unprecedented level of viral control the researchers discovered. Ribeiro is an assistant professor in the Pathology Advanced Translational Research Unit (PATRU) in the Department of Pathology and Laboratory Medicine at Emory School of Medicine, Ghneim is a project director for PATRU, and ten Caten is a bioinformatician at PATRU.

According to Sekaly and Paiardini, most studies that have tested immune approaches to curing HIV have been descriptive, without providing mechanisms that could explain the success or failure of the interventions. Thanks to the team’s deep expertise, the researchers were able to approach this study differently, taking the time to identify the molecular mechanisms of action, which will be fundamental information that the team can apply to other cure studies and immune interventions.

The research team is already planning future studies, including to better understand several pathways identified by the researchers in this study. These include innate immune, metabolic, and epigenetic pathways and their combinations that are associated with viral control after treatment ends. The team intends to develop and test interventions to induce an immune response that can intercept rebounding virus and provide long-term control of HIV and SIV when antiretroviral therapy is interrupted.