A University of Nebraska Medical Center scientist is part of a research team that has shown that they can achieve sustained control of SIV (simian immunodeficiency virus) infection in an animal model by supplementing antiretroviral drugs with an antibody during and after drug treatment. SIV is the animal version of HIV (human immunodeficiency virus), the virus that causes AIDS in humans.
Siddappa Byrareddy, Ph.D., an associate professor in the department of Pharmacology and Experimental Neuroscience at UNMC, is a co-first author of the journal article that is being released today in the journal Science.
“It is incredible to note that the virus remission was controlled in the animal model for such an extended period of time, and if we learn the mechanisms behind such control it will aid in developing an HIV cure, which is our ultimate goal,” Dr. Byrareddy said.
Sustained control means that when antiretroviral drugs were stopped, the virus did not re-emerge and cause disease. This was the first consistent demonstration of post-treatment immune control in an animal model infected with SIV, without previous vaccination. Long-term post-treatment control of HIV has been reported in only a handful of people treated soon after infection.
Members of the research team at the Department of Pathology, Emory University School of Medicine and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, report that while the virus is still present it has stayed below the limit of detectability in the blood, lasting almost two years after withdrawal of antiretroviral drugs.
The antibody the team used was designed to stop virus susceptible immune cells from entering intestinal tissues, a hot spot of damage during acute HIV and SIV infection. An analogous human antibody called vedolizumab was FDA-approved for the treatment of Crohn’s disease and ulcerative colitis in 2014. Based on the current findings, a pilot clinical trial, testing the safety of vedolizumab and its effect on HIV in people infected with the virus, has begun at NIAID.
“This comes from an idea I had many years ago: stopping CD4+ T cells from circulating into the gut may protect them during acute infection,” said senior author Aftab Ansari, Ph.D., professor of pathology and laboratory medicine at Emory University School of Medicine and Yerkes National Primate Research Center. “But how it precisely works in regulating viral replication is still far from clear. The antibody therapy appears to have helped the entire immune system.”
Several questions remain. How long can apparent remission last? Which parts of the immune system are most important for viral control? And what differences between this experiment and HIV infection of humans might impede translation of this finding into the clinic?
More than a million people in the U.S. and more than 35 million worldwide are living with HIV, many of them for years. Although antiretroviral drugs can suppress viral replication, residual low-level of infection and the drugs themselves still negatively affect health. The virus integrates into the DNA of immune cells and is thought to lurk in hard-to-eradicate reservoirs.
In the Science paper, the antibody the team used is against α4β7 integrin, which helps T cells find their way to intestinal lymphoid tissues. In 2008, NIAID researchers identified α4β7 integrin as a cell surface molecule involved in the association of the virus envelope with CD4+ T cells, but the antibody does not appear to directly block viral entry. Previous research has shown that the administration of the same antibody can block SIV transmission.
One possibly important difference between this experiment and HIV infection is that the animal model was infected for just five weeks, before beginning a three-month course of antiretroviral drugs. People usually don’t discover they are HIV-positive so soon after infection.
“This finding could become a blueprint for an alternative therapy for HIV, which could make it so someone would not need to continuously take anti-retroviral drugs,” Dr. Ansari said. “It could also help us craft more effective vaccines. We need to know more about how α4β7 antibody treatment exerts its effects.”
Dr. Byrareddy added, “This kind of therapy is urgently needed for HIV, since antiretroviral drugs alone cannot efficiently reach gut lymphoid tissues.”
Other co-first authors of the paper are James Arthos, Ph.D., and Claudia Cicala, Ph.D. both of the Laboratory of Immunoregulation. Drs. Arthos and Cicala worked under the overall direction of co-author Anthony Fauci, M.D., director of NIAID. The study was conducted at Yerkes National Primate Research Center at Emory University. Collaborators at University of Maryland, University of Michigan and the German Primate Center contributed to the paper.
The research was supported by the National Institute of Allergy and Infectious Diseases (AI098628, AI111907, Intramural) the National Institute of Child Health and Human Development (RO1HD077260), the Food and Drug Administration (U01FD005266) and the National Institutes of Health’s Office of Research Infrastructure Programs (Primate centers: 51OD11132).
We are Nebraska Medicine and UNMC. Our mission is to lead the world in transforming lives to create a healthy future for all individuals and communities through premier educational programs, innovative research and extraordinary patient care.