Scientists at the National Institutes of Health (NIH) and Emory University have experimentally induced sustained remission of SIV, the simian form of HIV, in infected monkeys. The animals' immune systems have been suppressing the virus to undetectable levels for as long as 23 months since the monkeys completed an investigational treatment regimen. In addition, the regimen has led to the near-complete replenishment of key immune cells that SIV had destroyed, something unachievable with antiretroviral therapy (ART) alone. The findings will be published in the Oct. 14 issue of the journal Science.
"Our data suggest that the immune systems of these animals are controlling SIV replication in the absence of antiretroviral therapy," said Anthony S. Fauci, M.D., who co-led the study as chief of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. "The experimental treatment regimen appears to have given the immune systems of the monkeys the necessary boost to put the virus into sustained remission. The precise mechanisms of this effect are unclear and will be actively pursued since they could have important implications for the control of HIV infection in humans in the absence of ART. At this point it is also unclear whether the findings of the newly reported animal study will translate into a clinical benefit for HIV-infected people." Dr. Fauci also is director of NIAID, the primary funder of the research.
The investigational treatment regimen consisted of 90 days of ART combined with 23 weeks of treatment with a laboratory-derived monkey antibody against a cellular receptor called alpha4beta7 integrin. This antibody is similar to the human drug vedolizumab, which is approved by the U.S. Food and Drug Administration for treating ulcerative colitis and Crohn's disease.
When a SIV-infected monkey or an HIV-infected person receives ART, the therapy can suppress the virus to undetectable levels. Yet the virus still lurks silently in the genetic material of infected immune cells, known as viral reservoirs, even when suppressed. If ART is discontinued, SIV or HIV rapidly rebounds to high levels within a few weeks. Thus, treatment for HIV today involves taking ART every day for life. Although ART dramatically improves health overall and prolongs life, daily ART can be a challenge to stick to and also can have side effects over time.
"The new findings suggest an alternative form of HIV therapy that may eliminate a requirement for lifelong daily ART, potentially improving the quality of life for people living with the virus and reducing the staggering, unmet cost of antiretroviral therapy for the 37 million people worldwide who need it," said Aftab A. Ansari, Ph.D., senior author of the paper and co-leader of the study. Dr. Ansari is a professor of pathology and laboratory medicine in the Department of Pathology and Laboratory Medicine at Emory University School of Medicine and a research associate at Emory's Yerkes National Primate Research Center in Atlanta.
Vedolizumab consists of an antibody to alpha4beta7 integrin, a receptor that is present at high levels on the immune-system cells that SIV and HIV preferentially infect. One function of this antibody is to prevent these immune cells from homing to gastrointestinal tissues, a major site of SIV and HIV replication and viral reservoir formation early in infection. A critical unanswered question, and the subject of ongoing research, is precisely how treatment with the alpha4beta7 antibody led to the regulation of SIV replication in the study monkeys.
"If we could figure out how the antibody works, then an effective HIV vaccine could be modeled on that mechanism," said Dr. Ansari. "That is the most important implication of our findings."
In the newly published experiment, investigators infected 18 rhesus macaques housed at the NIH-supported Yerkes Research Center with a disease-causing clone of SIV. Five weeks after infection, all the animals began receiving a 90-day course of daily ART. In addition, nine weeks after infection, 11 monkeys began receiving infusions of the investigational treatment antibody every three weeks while the other seven monkeys began receiving infusions of a placebo antibody. The infusions continued for 23 weeks. At the 32nd week after infection, all treatment ceased.
All 18 monkeys fully suppressed SIV by their third week on ART. Once the infusions began, three monkeys developed antibodies against the investigational treatment antibody and were excluded from further study. After the 15 remaining monkeys stopped receiving ART, SIV rebounded to high levels in the seven control animals within two weeks and remained high. Among the eight monkeys who received the investigational antibody infusions, SIV rebounded temporarily in six of them, but they regained control of the virus within four weeks. The virus never rebounded in the other two animals. These eight monkeys have continued to suppress SIV to undetectable levels in both the blood and gastrointestinal tissues for as long as 23 months since all treatment ended.
Since it is unclear whether the findings of this monkey study will translate into a clinical benefit for HIV-infected people, NIAID researchers recently began an effort to determine whether short-term treatment with vedolizumab in combination with ART can generate sustained HIV remission in such individuals. Sustained HIV remission, also known as a "functional cure," refers to the outcome of a treatment or therapeutic vaccination that induces prolonged, undetectable levels of HIV viremia without ART. The study investigators are hopeful that combining short-term vedolizumab treatment with ART will be as effective at suppressing HIV replication following withdrawal of ART in people as it appears to be at suppressing SIV replication in monkeys. A small, early-phase clinical trial testing the treatment regimen in HIV-infected people has already begun at the NIH Clinical Research Center in Bethesda, Maryland (ClinicalTrials.gov Identifier: NCT02788175). The study is testing whether a 30-week course of vedolizumab is safe and tolerable and allows study participants' immune systems to control the virus when they temporarily stop taking ART. Preliminary results are expected by the end of 2017 with further data becoming available into 2018.
Collaborating on the newly reported research with investigators at NIAID and Emory University were scientists at the Centre for the AIDS Program of Research in South Africa, Georgia Institute of Technology College of Engineering, Johns Hopkins School of Medicine, the German Primate Research Center, University of Maryland School of Pharmacy and University of Michigan. These organizations and the NIH Office of Research Infrastructure Programs also provided financial support.
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Reference: SN Byrareddy, et al. Sustained virologic control in SIV+ macaques following short term ART and alpha4beta7-mAb treatment. Science DOI: 10.1126/science.aag1276 (2016).