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

Viral Load HIV infection What is CD4 Posts
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, do Instituto Nacional de Alergia e Doenças Infecciosas (NIAID) e seus colegas, anunciaram que haviam induzido a remissão sustentada de SIV em macacos tratados com terapia anti-retroviral (ART) mais terapia de anticorpos. Macacos tratados não só tinham viral load indetectável por até dois anos após a interrupção da ART, mas também mostraram reabastecimento das principais células imunes no intestino.

The researchers used a “primalized version” 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.

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Logo após a infecção, o SIV e o HIV estabelecem reservatórios em células T CD4 de longa duração, onde o material genético viral pode permanecer indefinidamente em estado de inatividade. ARTE mantém a replicação viral sob controle, mas uma vez que as drogas são paradas o vírus reativa e retoma seu ataque às células imunes. As células T no intestino são especialmente vulneráveis durante a infecção precoce.

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.

“Para fazer uma longa história curta, descobrimos quase por acaso que, sem o conhecimento de nós, a molécula alfa-4 beta-7 em células T CD4 é um receptor para o envelope HIV”, disse Fauci. No estudo relatado em outubro passado, entre os onze macacos tratados com infusões de anticorpos alfa-4 beta-7, dois mantiveram a supressão viral após parar a ART – o mais longo por quase dois anos de seguimento – enquanto outros seis experimentaram uma recuperação viral temporária seguida por Reabsorção. Em contraste, todos os sete macacos que receberam infusões com placebo sofreram um rebote prolongado de SIV de alto nível. “Foi uma descoberta surpreendente, mas não sabíamos qual era o mecanismo – sabíamos que o resultado era muito profundo”, lembrou 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 with alpha-4 beta-7 migrated to intestinal tissue in mice (which have MAdCAM1 compatible), whereas HIV without alpha-4 beta-7 did not. The same alpha-4 beta-7 antibody used in the monkey remission study potently blocked this gut homing, but a control antibody did not. And the virus with and without alpha-4 beta-7 did not migrate differentially to lymph and spleen tissue - the effect was seen only in the gut.

Based on these findings, the researchers concluded that “incorporation of alpha-4 beta-7 into HIV-1 virions may promote tropism and virus retention in intestinal tissues, which may affect transmission and pathogens. explain how vedolizumab antibody therapy 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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