Emory researchers are the first to demonstrate unprecedented control over SIV replication and the decay of viral reservoirs by combining a stringent infection model with the interruption of antiretroviral therapy (ART). The success of this immune-based approach follows the research team’s identification of the mechanisms of action for PD1 and IL-10, molecules known to regulate HIV persistence and immune dysfunction.
The research results are reported today in Natural immunology.
“This is an important advance in the fight to achieve an HIV cure that will improve the lives of the 39 million people living with the disease,” said Rafick Sekaly, PhD, principal investigator of the R37 grant who funded this study and co-director of a 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, led us to develop this in vivo intervention in non-human primates (NHPs). Having this increased understanding of PD1 and IL-10 will our team is helping to develop improved approaches to repair immune deficiency, strengthen immune interventions to improve control of chronic infections, and even offer hope to better treat certain cancers,” he continued. Sekaly is also a professor and vice chair of translational medicine in the Department of Pathology at Emory School of Medicine, a distinguished scientist of the Georgia Research Alliance and a member of the Winship Cancer Institute’s Cancer Immunology Research Program.
Critical to a better understanding of PD1 and IL-10 was the NHP component of this study, which included 28 ART-treated, SIV-infected rhesus macaques, an animal model highly characterized for SIV infection. Mirko Paiardini, PhD, and Zachary Strongin led the study to develop the rigorous model of HIV/SIV infection, ART treatment, and immune-based intervention of anti-IL-10, a combination of anti-IL-10 plus anti-PD 1 or a placebo. After 14 months of ART, the researchers started the animals on immunotherapy treatment. Twelve weeks later, the researchers continued immunotherapy but discontinued ART. Nine of 10 monkeys given the combination treatment showed durable control of viral rebound lasting six months.
Paiardini is also co-leader and serves as a liaison to the principal investigator a Martin Delaney Collaboratory, the “Enterprise for Research & Advocacy to Stop & Eradicate HIV” (the ERASE HIV Collaboratory), the only one led by researchers from a National Primate Research Center (NPRC). In addition, Paiardini is department head of Microbiology and Immunology at the Emory NPRC, professor of Pathology and Laboratory Medicine at the Emory School of Medicine, and co-director of the Next Generation Therapeutics Scientific Working Group at the Emory Center for AIDS Research.
Strongin is a senior scientist, Discovery Immunology at Merck and a former graduate student in the Paiardini lab. Merck, the industrial partner for both the RID HIV and ERASE HIV Collaboratories, developed reagents specifically designed to target PD1 and IL10 molecules in non-human primate models.
Bonnie Howell, PhD, vice president and global head of quantitative life sciences and non-clinical pharmacology at Merck & Co., Inc. says: “Merck remains committed to supporting HIV research and translating concepts into life-saving products, including products with the potential to prevent, treat and treat HIV research and cure HIV.”
Sekaly considers the research collaboration between academia and industry, and the expertise of each team member, as the cornerstones of this research: “The scientific collaboration between RID HIV, ERASE HIV and Merck colleagues that led to the unprecedented results of this research has led is an example of the purpose of the Martin Delaney Collaboratories – to accelerate HIV cure research by bringing researchers together to share resources, data and methodologies.
First author Susan Ribeiro, PhD, and her bioinformatics team, including Khader Ghneim, MS, and Felipe ten Caten, PhD, used their methodological expertise to develop a unique systems biology platform that allowed the research team to explore all facets and cells of the immune system to mine. answer. That comprehensive approach facilitated the team’s identification of novel immune-based mechanisms underlying the unprecedented level of viral control the researchers discovered. Ribeiro is an assistant professor in the Pathology Advanced Translational Research Unit (PATRU) of the Emory School of Medicine Department of Pathology & Laboratory Medicine, Ghneim is project director for PATRU, and ten Caten is a bioinformatician at PATRU.
According to Sekaly and Paiardini, most studies that have tested immune-based approaches to an HIV cure have been descriptive, without providing mechanisms that can explain the success or failure of interventions. With the team’s deep expertise, the researchers were able to approach this study differently, taking the time to identify molecular mechanisms of action, which will be fundamental information that the team can apply toward more healing studies and immune interventions.
The research team is already making plans for future studies, including better understanding several pathways the researchers identified in this study. These include innate immune, metabolic and epigenetic pathways and combinations thereof associated with controlling the virus after treatment ends. The team plans to develop and test interventions to induce an immune response capable of intercepting the rebounding virus and providing long-term control of HIV and SIV when ART is discontinued.
