Clues to how anti-integrin antibody suppresses SIV

In October 2016, Emory and NIAID researchers published results in Science that surprised the HIV/AIDS field.

They showed that treatment with an antibody, on top of antiretroviral drugs, could lead to long-term viral suppression in SIV-infected monkeys. A similar antibody is already approved for Crohn’s disease, and a clinical trial has begun at NIAID testing the effects in people living with HIV.

The HIV/AIDS field is still puzzling over a study led by Emory pathologist Tab Ansari.

All that was achieved even though HIV/AIDS experts are still puzzled by how the antibody works. Last week, Christina Guzzo,with NIAID director Anthony Fauci’s lab, presented new data at the Conference on Retroviruses and Opportunistic Infections in Seattle that provide some clues. But the broader issue of “what is the antibody doing?” is still open.

Let’s back up a bit. The antibody used in the Science paper targets a molecule called integrin alpha 4 beta 7, usually described as a “gut homing receptor” for CD4+ T cells, which are ravaged by HIV and SIV infection.  Study leader Aftab Ansari (right) and Fauci have both said their idea was to stop T cells from circulating into the gut, a major site of damage during acute viral infection.

Integrin alpha 4 beta 7 was also known to interact with the HIV envelope protein. Accordingly, it is possible to imagine some possibilities for what an antibody against integrin alpha 4 beta 7 could be doing: it could be driving T cells to different places in the body or affecting the T cells somehow, or it could be interfering with interactions between SIV and the cells it infects.

The new data from NIAID say that integrin alpha 4 beta 7 is found on the virus itself. This finding makes sense, because SIV and HIV are enveloped viruses — they steal the clothes of the cells they infect and emerge from. [Integrin alpha 4 beta 7 also appears to help the virus be more infectious in the gut, Guzzo’s presentation says.]

So a third possibility appears: the anti-alpha 4 beta 7 antibody is mopping up virus. Perhaps it’s acting like a virus-neutralizing antibody or the anti-CD4 antibody ibalizumab — CD4 is the main viral receptor on T cells. It could explain why the anti-integrin antibody’s effect is so durable; HIV/SIV can mutate to escape neutralizing antibodies directed against the viral envelope protein, but it can’t mutate the clothes it steals!

NIAID researchers don’t consider this to be the end of the story. Their press release says: “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.”

On Monday, Elena Martinelli, who previously investigated integrin alpha 4 beta 7 in Fauci’s lab, visited Emory as a faculty candidate. In her talk, she described her related work (published in PLOS Pathogens) at the Population Council’s Center for Biomedical Research. Her group had examined small molecule drugs that also block integrin alpha 4 beta 7, but found that they didn’t interfere with viral infection in the same way an antibody did. This appears to be because the antibody interacts with the integrin molecule in a different way.

In the context of viral infection, Martinelli suggested that the anti-integrin antibody may be pushing the immune system toward a “tolerogenic state“. Lab Land is looking forward to more information on this topic.

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Posted on by Quinn Eastman in Immunology Leave a comment

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Quinn Eastman

Science Writer, Research Communications
qeastma@emory.edu
404-727-7829 Office

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