National Institutes of Health (NIH) scientists provide an explanation for how an anti-alpha-4 beta-7 antibody treatment resulted in sustained remission of SIV in a monkey experiment.
With 1.2 million individuals living with HIV in the United States alone, researchers are always working to better understand the virus and come up with new, innovative ways to prevent and treat an infection that continues to plague individuals around the world.
To this end, new research coming out of the National Institutes of Health (NIH) is offering a closer look at the protein alpha-4 beta-7. Researchers believe that the presence of the protein, found on the surface of both HIV and simian immunodeficiency virus (SIV)—a virus that causes AIDS-like symptoms in monkeys—may provide an explanation as to why, in past experiments, a “laboratory-derived monkey” antibody—comparable to the “human drug” vedolizumab—protected monkeys from SIV infection.
In October 2016, the scientists reported success in obtaining “sustained SIV remission” in monkeys through the use of the aforementioned antibody. A report that was presented February 15 at the Conference on Retroviruses and Opportunistic Infections in Seattle, not only revisited these experiments, but provided additional insight regarding the mechanism behind the scientists’ past observations.
According to a press release, “Scientists have known that alpha-4 beta-7 integrin is a gut-homing receptor present at high levels on the immune-system cells that HIV and SIV preferentially infect.” In this new research, the scientists discovered that as “maturing” HIV and SIV particles leave an infected cell, they obtain the protein alpha-4 beta-7; the researchers feel that these findings may provide a “new target” that can be used in HIV prevention and treatment efforts.
In the press release, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases and co-author of the report, explained that originally, the research team thought that the antibody would “attack alpha-4 beta-7 on immune cells and reduce their movement to the gut, where HIV and SIV typically decimate the cells early in infection.”
However, this was not the case.
Dr. Fauci explained, “Instead, our team found that anti-alpha-4 beta-7 antibody binds not only to cells but also to HIV and SIV. This likely explains at least in part our previous observation that SIV-infected monkeys treated with antibody to alpha-4 beta-7 and antiretroviral therapy controlled the virus very effectively long after all treatment ended.”
In studies that were conducted between 2014 and 2016, the scientists found that the antibody, when used against alpha-4 beta-7, did two important things: it reduced SIV transmission to monkeys that were not infected with the virus and “induced sustained SIV remission” those infected. In this current study, Dr. Fauci and his team focused their efforts on obtaining an explanation for these findings.
According to the press release, when it comes to obtaining their viral envelopes, both HIV and SIV get them from the membranes of cells that they leave; cellular proteins are also caught in this process. The team of scientists, led by Paolo Lusso, MD, PhD, chief of the Viral Pathogenesis Section in LIR, explored this formation even further. They found that “HIV buds from membranes of immune cells precisely where alpha-4 beta-7 is concentrated and incorporates alpha-4 beta-7 into its envelope protein.” This means that the virus actually “hijacks” alpha-4 beta-7 and uses it to create a stronger attack on the immune system.
Following these findings, the research team, including Dr. Lusso and Dr. Fauci, set out to gain a better understanding on how prevalent alpha-4 beta-7 is on the HIV envelope and just how it functions. To do this, they conducted a number of experiments. In a mouse model they were able to show that HIV “bearing the protein homes to the gut.” In cell culture, they demonstrated that when HIV bears the protein, it is “dramatically more efficient” in infecting “alpha-4 beta-7-recognizing gut cells and their neighbors,” than when HIV does not have the protein.
Furthermore, the researchers collected blood samples “at multiple time points” from 33 HIV-positive individuals as well as 12 SIV-positive monkeys. They found that all of the samples contained some measure of the virus bearing the protein alpha-4 beta-7. According to the press release, “The percentage of virus particles with the protein was greatest in blood samples taken during the early stages of infection, when the virus multiplies in the alpha-4 beta-7-rich immune cells of the gut.”
These findings suggest that when it comes to the initial phase of HIV infection, the alpha-4 beta-7 protein is “critical;” which means that the protein is a key factor in “the subsequent development of HIV disease.”
The scientists want to take their research a step further by proving that alpha-4 beta-7 presence on SIV is a good explanation for how the anti-alpha-4 beta-7 antibody worked to protect the monkeys in the earlier experiments from SIV infection.
In the meantime, participants are currently being enrolled into an early-phase clinical trial, based at the NIH Clinical Research Center in Bethesda, Maryland, to ascertain if a short-term treatment is capable of creating sustained HIV remission in HIV-positive individuals. The treatment? A combination of vedolizumab—the human drug that is similar to the anti-alpha-4 beta-7 antibody—and antiretroviral therapy. In this trial, researchers will test if a 30-week course of vedolizumab will allow for sustained control of HIV when participants temporarily cease antiretroviral therapy; preliminary results can be expected by the end of the year.