November 9, 2015
Restores intestinal immune cells, reduces residual inflammation
Lisa Newbern, 404-727-7709, email@example.com
Antiretroviral drugs can suppress HIV for years, but a residual inflammatory imbalance contributes to health problems in individuals who are infected with the virus. A novel combination treatment aimed at repairing the immune system has shown encouraging effects in a nonhuman primate model of HIV infection, both before and after a course of antiretroviral drug treatment.
The results are published in today’s online edition of the Journal of Clinical Investigation and are scheduled for publication in the December 2015 issue.
Scientists at Yerkes National Primate Research Center, Emory University, were testing the effects of a fusion protein based on the immunity stimulator IL-21. They found that when combined with antiretroviral drugs, IL-21 could help restore certain types of intestinal immune cells, which are depleted by SIV (simian immunodeficiency virus) infection and thought to be important for mucosal integrity.
IL-21 has been tested in clinical trials with people fighting skin and kidney cancer, but, so far, not in people who have HIV.
“We found IL-21 is effective at reducing residual inflammation and improving the reconstitution of Th17 and Th22 cells, which are critical for intestinal immunity,” says senior author Mirko Paiardini, PhD, assistant professor of pathology and laboratory medicine at Yerkes National Primate Research Center and Emory University School of Medicine, and a member of the Emory Vaccine Center.
Co-first authors of the paper are postdoctoral fellow Luca Micci, PhD, and research specialist Emily Ryan.
In the study, the researchers treated SIV-infected rhesus macaques with the IL-21 fusion protein starting two months after they were infected. All 16 monkeys, eight IL-21-treated and eight controls, received a combination of antiretroviral drugs.
Antiretroviral drug treatment continued for seven months and then was withdrawn. IL-21 was given in three once-per-week cycles, including one cycle just after antiretroviral drugs were stopped.
After drugs were stopped, SIV still reappeared in both the IL-21-treated group and controls. However, in IL-21-treated animals, levels of SIV RNA in the blood stayed at a level that was five times less than in controls, extending out to eight months. A similar effect was seen on viral DNA levels in intestinal tissues and blood CD4 T cells. In addition, IL-21 treatment appeared to have other benefits, in terms of both reduced immune activation and signs of improved antimicrobial immunity.
“This was an important test of the concept that an intervention that reduces immune activation during antiretroviral therapy can also limit viral persistence. Our data provide a rationale for additional preclinical studies on IL-21 as part of a novel combination strategy aimed at limiting the size of the latent viral reservoir and contributing to a remission or functional cure,” says Paiardini.
Yerkes research collaborators for this study included Guido Silvestri, MD, chief of microbiology and immunology, and Francois Villinger, DVM/PhD. Additional collaborators included Jacob Estes and Jeffrey Lifson, AIDS Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.; Jason Brenchley, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and Nicolas Chomont and Rémi Fromentin, Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, and Centre de Recherche du CHUM, Montreal.
The research was supported by amfAR - the Foundation for AIDS Research, the National Institute of Allergy and Infectious Diseases (R01AI084836, R01AI110334 and R33AI104278), the Emory Center for AIDS Research and the NIH Director’s Office of Research Infrastructure Programs (Primate centers: P51OD011132).
Established in 1930, the Yerkes National Primate Research Center paved the way for what has become the National Institutes of Health-funded National Primate Research Center (NPRC) program. For more than eight decades, the Yerkes Research Center has been dedicated to conducting essential basic science and translational research to advance scientific understanding and to improve human health and well-being. Today, the Yerkes Research Center is one of only eight NPRCs. The center provides leadership, training and resources to foster scientific creativity, collaboration and discoveries, and research at the center is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate, quality animal care.
In the fields of microbiology and immunology, infectious diseases, pharmacology and drug discovery, transplantation, neurologic and psychiatric diseases, as well as behavioral, cognitive and developmental neuroscience, Yerkes scientists use innovative experimental models and cutting-edge technologies to explore and test transformative concepts aimed at: preventing and treating viral diseases such as AIDS; designing novel vaccines for infectious diseases such as malaria and tuberculosis; enhancing the potential of organ transplantation and regenerative medicine; discovering new drugs and drug classes through high-throughput screening; defining the basic neurobiology and genetics of social behavior and developing new therapies for disorders such as autism and drug addiction; understanding the biology of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases; and advancing knowledge about the evolutionary links between biology and behavior.
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.