Research helps explain how antibody treatment led to lasting HIV-like virus remission

February 15, 2017
Diagrammatical representation of the molecular structure of HIV-1 protease complexed with the inhibitor indinavir. Credit: Public Domain

Scientists at the National Institutes of Health have found that the presence of the protein alpha-4 beta-7 integrin on the surface of HIV and its monkey equivalent—simian immunodeficiency virus, or SIV—may help explain why an antibody protected monkeys from SIV in previous experiments.

In October 2016, researchers reported that they had achieved sustained SIV remission in monkeys using a monkey antibody 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. The mechanism behind this observation has been unclear, but a new report presented today at the Conference on Retroviruses and Opportunistic Infections in Seattle provides clues.

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 the new study, scientists found that maturing HIV and SIV particles acquire alpha-4 beta-7 as they emerge from an infected cell, presenting researchers with a new target for HIV prevention and treatment and shedding light on how HIV disease develops.

"We expected the antibody to attack alpha-4 beta-7 on and reduce their movement to the gut, where HIV and SIV typically decimate the cells early in infection," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, who co-authored the report as chief of the Laboratory of Immunoregulation (LIR).

"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."

Studies conducted by Dr. Fauci and colleagues in his laboratory and at Emory University, Atlanta, between 2014 and 2016 showed that a laboratory-derived monkey antibody against alpha-4 beta-7 reduced the transmission of SIV to uninfected monkeys and induced sustained SIV remission in infected monkeys. Dr. Fauci's team undertook the current study to understand why.

HIV and SIV acquire their envelopes from the membranes of the cells from which they emerge, capturing some cellular proteins in the process. Led by Paolo Lusso, M.D., Ph.D., chief of the Viral Pathogenesis Section in the LIR, researchers discovered 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 . In this way, the virus hijacks a cellular protein to sharpen its assault on the immune system.

Subsequently, Drs. Lusso, Fauci and colleagues conducted experiments to understand the function and prevalence of the alpha-4 beta-7 protein on the HIV envelope. They demonstrated in a mouse model that HIV bearing the protein homes to the gut. They also showed in cell culture that HIV infects alpha-4 beta-7-recognizing gut cells and their neighbors in a dramatically more efficient manner when the virus bears the protein than when it does not.

Finally, they demonstrated that blood samples taken from 33 HIV-infected people and 12 SIV-infected monkeys at multiple time points all had at least some virus bearing alpha-4 beta-7. The percentage of virus particles with the protein was greatest in blood samples taken during the early stage of infection, when the virus multiplies in the alpha-4 beta-7-rich immune cells of the gut.

Based on these findings, the researchers believe the protein is critical to the initial phase of infection, which has a major influence on the subsequent development of HIV disease.

The scientists' next step is to conduct a study to try to prove that the presence of alpha-4 beta-7 on SIV explains the protective effect of the anti-alpha-4 beta-7 antibody observed in the earlier monkey experiments.

Meanwhile, Dr. Fauci and other NIAID researchers are enrolling participants in a clinical trial to determine whether short-term treatment with vedolizumab in combination with antiretroviral therapy (ART) can generate sustained HIV remission in people living with HIV.

Explore further: Researchers achieve sustained viral remission in SIV infection

More information: Virion incorporation of alpha-4 beta-7 facilitates HIV-1 infection and intestinal homing. C. Guzzo, et al. Conference on Retroviruses and Opportunistic Infections, Feb. 15, 2017.

Related Stories

Immune-enhancing treatment may destabilize HIV reservoirs

July 21, 2016

Although antiretroviral therapy (ART) can reduce the amount of HIV in the blood to an undetectable level in most chronically infected people, it cannot eliminate reservoirs of HIV that persist in latently infected immune ...

Breast cancer study predicts better response to chemotherapy

December 15, 2016

It is known from previous research that the ER-beta estrogen receptor often has a protective effect. A new study from Lund University in Sweden has found that this effect is more pronounced in patients that undergo chemotherapy.

Reprogramming cells to fight diabetes

February 22, 2013

For years researchers have been searching for a way to treat diabetics by reactivating their insulin-producing beta cells, with limited success. The "reprogramming" of related alpha cells into beta cells may one day offer ...

Recommended for you

Scientists zoom in on AIDS virus hideout

March 15, 2017

French scientists said Wednesday they had found a way to pinpoint elusive white blood cells which provide a hideout for the AIDS virus in people taking anti-HIV drugs.

HIV hijacks common cells to spread infection

February 16, 2017

Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), together with collaborators in Europe, discovered that a common type of cell within the human reproductive and intestinal tracts ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.