Targeted Immune Intervention and Stopping ART in Model of SIV Infection Leads to Control of Viral Replication and Reservoirs

September 12, 2024

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Lisa Newbern

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Emory researchers are the first to show unprecedented control of SIV replication and decay of viral reservoirs by combining a stringent model of infection 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 study results are reported today in Nature Immunology.

"This is a major advancement in the fight to reach an HIV cure, which will improve life for the 39 million people who live with the disease," says Rafick Sekaly, PhD, lead investigator of the R37 grant that 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 that started more than 15 years ago led us to develop this in vivo intervention in nonhuman primates (NHPs). Having this increased understanding of PD1 and IL-10 will facilitate our team developing improved approaches to restore a deficient immune system, bolster immune interventions to improve control of chronic infections and even offer hope to better treat certain cancers," he continues. Sekaly is also professor and vice-chair of translational medicine in the Department of Pathology at the Emory School of Medicine, a Georgia Research Alliance eminent scholar and a member of the Cancer Immunology Research Program at Winship Cancer Institute.

Critical to better understanding 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 research to develop the stringent 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 the immunotherapy, but stopped ART. Nine of the ten monkeys that received the combination treatment showed durable control of viral rebound that lasted for six months.

Paiardini also co-leads and serves as contact principal investigator for a Martin Delaney Collaboratory, the "Enterprise for Research & Advocacy to Stop & Eradicate HIV" (the ERASE HIV Collaboratory), which is the only one researchers at a National Primate Research Center (NPRC) are leading. In addition, Paiardini is Microbiology and Immunology division chief at the Emory NPRC, a 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 senior scientist, Discovery Immunology at Merck and a former graduate student in the Paiardini lab. Merck, the industry partner for both the RID HIV and the ERASE HIV Collaboratories, developed reagents specifically designed to target PD1 and IL10 molecules in nonhuman primate models.

Bonnie Howell, PhD, vice president and global head of quantitative biosciences & nonclinical pharmacology at Merck & Co., Inc. says, "Merck remains committed to supporting HIV research and translating concepts into lifesaving products, including those with the potential to prevent, treat and cure HIV."

Sekaly credits the research collaboration between academia and industry, and the expertise of each team member, as the cornerstones of this study: "The scientific collaboration among RID HIV, ERASE HIV and Merck colleagues that led to the unmatched results of this study exemplifies the goal of the Martin Delaney Collaboratories – to expedite HIV cure research by bringing together researchers 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 methodology expertise to develop a unique systems biology platform that enabled the research team to mine all facets and cells of the immune response. That comprehensive approach facilitated the team's identification of novel immune based mechanisms that underlie the unprecedented level of viral control the researchers discovered. Ribeiro is assistant professor in the Pathology Advanced Translational Research Unit (PATRU) in the Emory School of Medicine Department of Pathology & Laboratory Medicine, Ghneim is director of projects for PATRU, and ten Caten is a bioinformatician at PATRU.

According to Sekaly and Paiardini, most studies that have tested immune-based approaches toward an HIV cure have been descriptive without providing mechanisms that can explain the success or failure of interventions. With the depth of expertise on the team, the researchers were able to approach this study differently, taking time to identify molecular mechanisms of action, which will be foundational information the team can apply toward more cure studies and immune interventions.

The research team is already making plans for future studies, including further understanding several pathways the researchers identified in this study. These include innate immune, metabolic and epigenetic pathways and combinations thereof that are associated with controlling the virus after ending treatment. The team intends to develop and test interventions to induce an immune response capable of intercepting rebounding virus and providing long-term control of HIV and SIV when ART is discontinued.

Acknowledgements

The publication contents are those of the author(s) and do not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. government. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding:

The research reported in this release is supported in part by the by the Emory National Primate Research Center's base grant from the NIH Office of the Director, an NIH/NIAID Merit Award and four other grants:

Grant amounts:

  • NIH/OD: P51OD011132 $10,751,414/year for 5 years
  • NIH/NIAID: Merit Award R37 AI141258, $738,490/FY24
  • NIH/National Cancer Institute: 75N91019D00024, $63,948/FY24
  • CFAR: P30 AI050409: $2,249,949/FY24
  • 1UM1AI164561-01: $5,001,807/FY21
  • UM1AI164562: $4,667,081/FY24

Note: Only a portion of the amounts listed above supported the research reported in this news release.


DOI: 10.1038/s41590-024-01952-4


Dedicated to discovering causes, preventions, treatments and cures, the Emory National Primate Research Center (ENPRC), part of Emory University's Robert W. Woodruff Health Sciences Center, is fighting diseases and improving human health and lives worldwide. The center, one of only seven NPRCs the National Institutes of Health (NIH) partially funds, is supported by approximately $94 million in research funding (all sources, fiscal year 2024). ENPRC researchers are making landmark discoveries in microbiology and immunology; neurologic diseases; neuropharmacology; behavioral, cognitive, and developmental neuroscience; and psychiatric disorders. Since 1984, the center has been fully accredited by the AAALAC International, regarded as the gold seal of approval for laboratory animal care.