Emory Researchers Closer to Understanding Mechanisms that Support HIV Persistence
June 9, 2022
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Lisa Newbern
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While antiretroviral therapy (ART) has greatly reduced HIV-related death and disease symptoms, a cure remains elusive, and the virus remains a threat because of the way it takes cover in certain immune cells and rapidly rebounds in the absence of ART. Researchers at the Emory National Primate Research Center (EPC) are working to lower HIV persistence and recently discovered a well-known anti-inflammatory protein, called interleukin-10, may be responsible for helping sustain cellular reservoirs that shelter the virus.
The research team says this finding, which was reported in The Journal of Clinical Investigation (JCI), could lead to treatments that block the effects of interleukin-10 and, therefore, reduce viral persistence.
People who live with HIV must take drug cocktails perpetually to keep the virus under control or they risk disease resurgence and death. "To end the burden and expense of long-term medication and to improve quality of life, our research team studied how viruses like HIV are able to hide in the body," says Mirko Paiardini, PhD, senior author of the study and research team lead. "We discovered interleukin-10 has a second critical role; in addition to serving as an anti-inflammatory substance, it supports maturation and survival of cells known to harbor HIV and SIV." Paiardini is a core researcher in the Microbiology and Immunology Division at the EPC and a Professor of Pathology and Laboratory Medicine at the Emory School of Medicine.
The role of interleukin-10 in favoring HIV persistence is a critical focus of the Enterprise for Research and Advocacy to Stop and Eradicate (ERASE) HIV team, one of the newly awarded Martin Delaney Collaboratories for HIV Cure. In addition to Paiardini, this study includes other key members of the ERASE HIV team, including Emory researchers Rafick Sekaly, PhD, Susan Ribeiro, PhD, Deanna Kulpa, PhD, and Guido Silvestri, MD, as well as OHSU researcher Jacob Estes, PhD, and Merck researchers Bonnie Howell, PhD, and Dan Gorman.
Interleukin-10's main function to dampen the host's immune response after an infection is critical for protecting tissue from the damage of long-term inflammation. Paradoxically, it can also allow viruses to persist by limiting the immune system's defenses against them.
In the JCI paper, the researchers addressed two important questions: How does interleukin-10 regulate the survival of cells known to harbor HIV, and does blocking signaling of this protein reduce the persistence of the virus when used in combination with ART? The team worked with rhesus macaques, an established animal model for studying SIV infections as a proxy of HIV, to determine the answers.
During chronic infection, levels of interleukin-10 are elevated in plasma and correlate with SIV content found in T cell subtypes known to be important for viral persistence. The subtypes include CD4+ cells, called T follicular helper (TFH) cells, and are found in lymph nodes.
"When we looked at lymph node tissues, we found the vast majority of cells infected with SIV were within close proximity to cells expressing interleukin-10. This was the case in both chronically infected animals and in those treated with antiretroviral therapy," Paiardini says.
"This finding strongly suggests interleukin-10 signaling is critically involved in promoting the survival of the cells that harbor the virus, which is surprising because physiological levels of interleukin-10 increase only a small amount following infection," added co first author Justin Harper, MA.
To test whether blocking interleukin-10's signaling could lower the levels of SIV in lymph node tissue, the researchers treated six macaques that had received ART with an antibody against interleukin-10. Other research groups previously showed this tactic promotes clearance of virus in mouse models of chronic infection. The Emory team found the antibody significantly reduced the frequency of immune cells harboring SIV in the macaques' lymph nodes.
"This is the first study to test this approach in a nonhuman primate model," Paiardini notes. "It was limited by the short duration of antiretroviral therapy and the small sample size, but our findings suggest this is an area that warrants further study."
In collaboration with Merck & Co., the Emory researchers are continuing to pursue their studies through preclinical trials in nonhuman primates; the NIH is funding this research via an R37 grant to Sekaly (co senior author of the study) and the ERASE HIV grant to Paiardini, Silvestri and Kulpa. These studies are evaluating whether targeting interleukin-10, alone or in combination with strategies to synergistically improve immune function, represent a viable treatment approach for achieving viral remission in the absence of ART.
Funding:
The research reported in this release is supported in part by the by the Emory and Oregon National Primate Research Centers' base grants from the NIH Office of the Director, and divisions of the NIH, including the National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke and National Institute on Drug Abuse. The publication contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, NIH/HHS or the U.S. Government.
Grant amounts (direct + indirect):
NIH/OD
- P51OD011132, $10,751,414/year for 5 years
- U42OD011023, $1,531,512/year for 4 years
- P51OD011092, $13,153,537/year for 5 years
- 1S10OD025002-01, $145,716/year for 1 year
NIH/NIAID
- R01AI116379, $783,714/year for 5 years
- R21AI122380, $284,963/year for 2 years
- R37AI141258, $4,199,050 for 5 years
- NIH/NHLBI/NIDDK/NINDS/NIDA/NIAID
- UM1AI164562, $23.8 million for 5 years
NIH/NCRR
- R24RR016988, $3,604,736 for 10 years
NIH/NCI
- 75N91019D00024, $6.6 billion for 3 years
- HHSN261200800001E, $5,936,717,405 for 10 years
Note: The amounts listed above are for the full grants. Only a portion of each grants supported the research reported in this news release.
Dedicated to discovering causes, preventions, treatments and cures, the Emory National Primate Research Center (EPC), 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) funds, is supported by more than $88 million in research funding (all sources, fiscal year 2021). EPC 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.
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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.