Researchers have achieved significant control over SIV replication and the reduction of viral reservoirs by merging a precise model of infection with the interruption of antiretroviral therapy (ART). This immune-based strategy stems from the research group’s discovery of how PD1 and IL-10 function—these molecules are critical in regulating HIV persistence and immune dysfunction.
Emory researchers are pioneers in demonstrating remarkable control over SIV replication and the decline of viral reservoirs by integrating a rigorous infection model with the cessation of antiretroviral therapy (ART). Their success in this immune-focused approach results from a thorough understanding of PD1 and IL-10’s mechanisms of action, which are vital for managing HIV persistence and immune impairment.
The findings of their study are being published today in Nature Immunology.
“This represents a groundbreaking step forward in the quest for an HIV cure and will enhance the lives of the 39 million individuals living with this disease,” says Rafick Sekaly, PhD, lead investigator of the research supported by an R37 grant and co-director of the Martin Delaney Collaboratory for HIV Cure Research, titled “Reversing Immune Dysfunction for HIV-1 Eradication” (the RID HIV Collaboratory). “Our work on PD1 and IL-10, which began over 15 years ago, allowed us to create this in vivo intervention in nonhuman primates (NHPs). Understanding PD1 and IL-10 better will help us develop improved methods to revitalize a weakened immune system, enhance immune strategies for managing chronic infections, and may even present new options for treating certain cancers,” he explains. Sekaly also serves as a professor and vice-chair for translational medicine in the Department of Pathology at the Emory School of Medicine, is a Georgia Research Alliance eminent scholar, and is involved in the Cancer Immunology Research Program at Winship Cancer Institute.
A key aspect of comprehending PD1 and IL-10 involved the NHP portion of this research, which analyzed 28 ART-treated, SIV-infected rhesus macaques—an animal model with a well-documented history of SIV infection. Mirko Paiardini, PhD, and Zachary Strongin led the effort in crafting a stringent approach to studying HIV/SIV infection, ART treatment, and the immune-based intervention using anti-IL-10, either in combination with anti-PD-1 or with a placebo. Following 14 months of ART, the researchers began administering immunotherapy to the animals. After 12 weeks of immunotherapy, they ceased the ART. Notably, nine out of ten monkeys receiving the combined treatment exhibited lasting control over viral resurgence, enduring for six months.
Paiardini also co-leads and acts as the main contact principal investigator for another Martin Delaney Collaboratory, the “Enterprise for Research & Advocacy to Stop & Eradicate HIV” (the ERASE HIV Collaboratory), which is unique in that it is led by researchers from a National Primate Research Center (NPRC). Additionally, he is the Microbiology and Immunology division chief at the Emory NPRC, a professor in Pathology and Laboratory Medicine at 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 in Discovery Immunology at Merck and was formerly a graduate student in the Paiardini lab. Merck is the industrial collaborator for both the RID HIV and ERASE HIV Collaboratories and has developed reagents specifically targeting PD1 and IL10 in nonhuman primate studies.
Bonnie Howell, PhD, vice president and global head of quantitative biosciences & nonclinical pharmacology at Merck & Co., Inc., states, “Merck is dedicated to supporting HIV research and converting these concepts into life-saving solutions, including potential strategies for preventing, treating, and curing HIV.”
Sekaly attributes the success of this study to the collaboration between academic and industry partners, emphasizing the invaluable expertise from each team member: “The unparalleled results of this study are a testament to the scientific cooperation among RID HIV, ERASE HIV, and Merck. This collaboration illustrates the goal of the Martin Delaney Collaboratories—to accelerate HIV cure research through the sharing of resources, data, and methodologies.”
First author Susan Ribeiro, PhD, along with her bioinformatics team members Khader Ghneim, MS, and Felipe ten Caten, PhD, employed their advanced methodologies to create a distinctive systems biology platform. This facilitated their ability to analyze the complete immune response spectrum, which led to the discovery of novel immune mechanisms responsible for the exceptional level of viral control observed. Ribeiro is an assistant professor in the Pathology Advanced Translational Research Unit (PATRU) within the Emory School of Medicine’s Department of Pathology & Laboratory Medicine, while Ghneim directs projects at PATRU and ten Caten serves as a bioinformatician there.
According to Sekaly and Paiardini, many previous studies utilizing immune-based strategies for an HIV cure have been primarily descriptive and lacked an explanation for the success or failure of their approaches. With their combined expertise, the research team was able to uniquely address this study by spending time unraveling the molecular mechanisms at play, which will provide foundational insights for future studies aimed at HIV cure and immune interventions.
Looking ahead, the research group is already planning future investigations to delve deeper into several pathways identified in this work. These include innate immune pathways, metabolic pathways, and epigenetic combinations that can help control the virus after ART cessation. The team aims to devise and trial interventions designed to prompt an immune reaction capable of preemptively handling a rebounding virus, thus ensuring long-term management of HIV and SIV following the discontinuation of ART.
