HIV, SIV Surface Protein Causes Sustained Remission in SIV Monkeys

A specific protein found on the surface of HIV and simian immunodeficiency virus (SIV) may be responsible for how study monkeys administered an antibody treatment achieved sustained remission of SIV.

In an October 2016 study published in Science, investigators found that monkeys administered an antibody similar to the human drug vedolizumab (Entyvio) achieved sustained SIV remission. Vedolizumab is FDA-approved for the treatment of ulcerative colitis and Crohn’s disease.

Until recently, the mechanisms behind the study findings remained unclear. In a new report presented at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington, investigators may have found some clues.

Scientists have known that the protein alpha-4 beta-7 integrin is a gut-homing receptor found at high levels on immune system cells that HIV and SIV infect, according to the National Institutes of Health (NIH).

In the new study, NIH scientists found that mature HIV and SIV particles acquire alpha-4 beta-7 as they emerge from an infected cell, indicating a new target for HIV prevention and treatment. Furthermore, the findings provide further information on how HIV develops.

“We expected the antibody to attach alpha-4 beta-7 on immune cells and reduce their movement to the gut, where HIV and SIV typical decimate the cells early in infection,” said co-author Anthony S. Fauci, MD, director of the NIH’s National Institute of Allergy and Infectious Diseases. “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.”

Prior studies conducted by Dr Fauci and colleagues between 2014 and 2016 found that a laboratory-derived monkey antibody against alpha-4 beta-7 reduced the transmission of SIV in uninfected monkeys, and induced sustained SIV remission in infected monkeys. Dr Fauci’s team undertook the current study to understand why, according to the NIH press release.

The envelopes of HIV and SIV are acquired from the membranes of cells they have infected, obtaining some cellular proteins in the process. The investigators found that HIV buds from membranes of immune cells precisely where alpha-4 beta-7 is located, and incorporates the alpha-4 beta-7 into its envelop protein. This way, the virus can hijack the cellular protein to help battle the immune system. The study was led by Paolo Lusso, MD, PhD, chief of the Viral Pathogenesis Section in the Laboratory of Immunoregulation (LIR).

Subsequently, Drs Lusso, Fauci and colleagues conducted experiments to understand both the function and prevalence of the alpha-4 beta-7 protein on the HIV envelope, according to the press release.

The investigative team used an HIV mouse model to show that HIV donned with protein homes to the gut. In cell cultures, the investigators showed that when HIV bears the protein, it is able to infect alpha-4 beta-7 to recognize gut cells and their neighbors with more efficacy than when the virus does not.

The investigators also demonstrated that obtaining blood samples from 33 individuals with HIV and 12 monkeys with SIV at different time points all had at least some virus bearing the alpha-4 beta-7 protein.

The percentage of HIV particles with the protein was found to be highest in blood samples taken during the early stage of infection, the press release reported.

The study findings suggest that the protein is crucial to the initial phase of infection, which has a major influence on the subsequent development of HIV, the authors said.

Next, the investigators plan to conduct a study designed to prove that the presence of alpha-4 beta-7 on SIV explains the protective effect of the alpha-4 beta-7 antibody that was observed in the earlier monkey studies.

Currently, Dr Fauci and other NIAID investigators are enrolling participants in an early-phase clinical trial to determine whether short-term treatment with vedolizumab in combination with antiretroviral therapy (ART) can generate sustained remission in individuals with HIV. The study is examining the safety and tolerability of a 30-week regimen of vedolizumab in patients who temporarily stop taking ART.

Preliminary results are expected by the end of 2017 and additional data will be available in 2018, according to the press release.