Research helps explain how therapy with antibodies "Vedolizumab" sustained viral leads to remission

HIV virus particle structure

The HIV and its SIV monkey prime can take receptor alpha 4 beta-7 integrin on their outer envelope, which helps the virus to enter the intestinal cells during early infection, according to research presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle. This finding may help explain how an antibody against alpha-beta-4 7 produced sustained viral remission in monkeys.

Anthony Fauci of the National Institute of Allergy and Infectious Diseases (NIAID) and his colleagues announced that they had induced sustained remission of SIV in monkeys treated with antiretroviral therapy (ART) more antibody therapy. treated monkeys not only had an undetectable viral load by up to two years after discontinuation of ART, but also showed refueling of the main immune cells in the intestine.

The researchers used a version "primatised treatment of inflammatory bowel disease.

At the time of the report, the researchers said they did not know how the alpha-beta-4 7 antibody kept the virus under control.

At CROI Christina Guzzo NIAID presented results from laboratory studies that clarify the role of alpha-beta-4 7 in HIV infection and provides a mechanism for how an antibody that blocks the receptor may help control HIV and SIV. Dr. Guzzo attended a press conference at CROI, accompanied by Dr. Fauci via video.

People_living_with_HIV_AIDS_world_map

Soon after infection, SIV and HIV reservoirs CD4 establish long term T cells, which viral genetic material can remain indefinitely in idle state. ART maintains viral replication under control, but once the drugs are stopped the virus reactivates and resumes its attack on immune cells. T cells in the intestine are especially vulnerable during early infection.

Dr. Guzzo and Fauci explained that the alpha-beta-4 7 integrin receptor on T cells helps them migrate to the intestinal tissue. Previous studies have shown that cells that express alpha-4 beta-7 are highly susceptible to HIV infection, and that the locking alpha 4 beta-7 leads to reduced transmission of SIV (acquired immunodeficiency virus Simian) and lower load virus in monkeys.

"To make a long story short, we discovered almost by accident that, unbeknownst to us, the alpha-beta-4 7 molecule CD4 T cells is a receptor for the HIV envelope," Fauci said.

In the study reported last October, among the eleven monkeys treated with infusions of alpha-4 beta-7 antibodies, two maintained viral suppression after stopping ART - the longest for almost two years of follow-up - while six others experienced a viral recovery temporary followed by reabsorption. In contrast, all seven monkeys that received infusions of placebo experienced an extended rebound high level SIV.

"It was an amazing discovery, but we did not know what was the mechanism - we knew that the result was very deep," said Fauci.

Dr. Guzzo explained that the coating contains intestinal epithelial cells that express adhesion molecules, such ICAM1 and MAdCAM1, waiting to capture cells that express the appropriate receptors. MAdCAM1, which is largely confined to the intestine, looking alpha-beta-4 7 receiver, and thus attracts CD4 T cells bearing this receptor.

intestines

The latest research shows that the same mechanism can attract SIV or HIV itself to the intestine. As the particles newly created viruses out of a host cell they catch part of the cell membrane and their alpha-beta-4 7 receptors are incorporated into the viral envelope.

Dr. Guzzo's team found that alpha-beta-4 7 associated with the virus is functionally active, and is on the cell surface and binds readily to MAdCAM1. They then created virus particles modified with or without alpha-beta-4 7 and found that only the viruses carrying alpha-beta-4 7 was captured by MAdCAM1 and target cells infected in the laboratory.

Analyzing HIV-1 human patients, they found that the virus circulating consistently incorporates alpha-beta-4 7 during acute and chronic infection. Observing monkeys experimentally infected with SIV, they found that the incorporation of alpha-beta-4 7 was greater during the early infection.

Finally, they showed that HIV carrier of alpha-beta-4 7 migrated to intestinal tissue in mice (which have MAdCAM1 compatible), whereas HIV without alpha-beta-4 7 not. The same alpha-beta-4 7 antibody used in the monkey study remission potently blocked this gut homing, but a control antibody did not. And the virus with and without alpha-beta-4 7 not differentially migrate to lymph tissue and spleen - the effect was seen only in the intestine.

Based on these findings, the researchers concluded that "the incorporation of alpha-4 beta-7 in HIV-1 virions can promote tropism and virus retention in intestinal tissues, which may affect the transmission and pathogens The research helps explain how the therapy Vedolizumab antibodies leads to sustained viral remission

Translated by Claudio of Contents on the link Research helps explain how Vedolizumab antibody therapy leads to sustained viral remission

Liz Highleyman

Produced in collaboration with hivandhepatitis.com

Published: 23 2017 in March AIDSMAP.com

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Reference

C Guzzo et al. Virion incorporation of integrin alpha-beta-4 7: implications for HIV pathogenesis 1. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 64LB, 2017.

View the abstract on the conference website.

Watch the webcast of this presentation on the conference website.

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