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Study finds new path to HIV vaccines

JUNE 5, 2015 A newly discovered response that alerts the immune system to HIV infection has been reported by a team led by Sanford-Burnham Medical

Sanford-Burnham researchers find how to more fully activate immune system against HIV

This illustration indicates what may happen when an HIV vaccine is boosted with a drug that starts the PQBP1 immune response. Amplifying the response may cause more production antibodies to HIV.This illustration indicates what may happen when an HIV vaccine is boosted with a drug that starts the PQBP1 immune response. Amplifying the response may cause more production antibodies to HIV. — Sumit Chanda, Sanford-Burnham Medical Research Institute
 

A newly discovered response that alerts the immune system to HIV infection has been reported by a team led by Sanford-Burnham Medical Research Institute scientists.

HIV vaccines could be improved by incorporating this previously unknown molecular trigger, the scientists said in the study. It was published Thursday in the journal Cell.

A cellular protein called polyglutamine-binding protein 1, or PQBP1, binds to DNA produced by the virus and triggers an immune reaction. The response activates both of the immune system's two arms, the innate and adaptive systems. The innate system mounts a general response to infections; the adaptive immune system produces highly specific responses, including antibodies, that seek out and destroy a certain pathogen.

The conventional story of HIV infection centers on CD4 lymphocytes, white blood cells that HIV infects by latching onto cell surface receptors. So HIV therapeutic approaches often target this interaction.

However, HIV vaccines, which use viral proteins, pieces of DNA made by HIV, and other substances, don't provoke a powerful enough response to defeat the virus. At most, they provide a modest benefit, not enough to reliably prevent HIV infection and ultimately AIDS.

An HIV vaccine that not only targets the virus itself but also activates this newly discovered molecular mechanism could serve as an adjuvant, a substance that sends the immune response into higher gear, said Sumit Chanda, who was the paper's senior author. The first author was Sunnie M. Yoh, a postdoctoral fellow in Chanda's lab.

"One of the key parts of vaccines that people haven't really pursued is how to coax the innate immune system to recognize HIV and respond to it," Chanda said. "That's because we really didn't know what was going on, how the cells sense HIV and elicit innate immunity that triggers adaptive immunity. This opens up a new strategy, both for vaccine and adjuvant designs."

The goal of vaccines is to mimic infections without producing the disease itself, Chanda said. "The first thing the body has to do is recognize infection, and that's innate immunity. That in turn elicits an adaptive response that's very specific in making antibodies to HIV or flu or whatever. We really didn't understand this innate immunity aspect of things ... now that we understand, we can open up a second front in trying to come up with a vaccine."

The newly discovered interaction takes place in dendritic cells, which control the innate immune response and also activate the adaptive immune response. HIV is a retrovirus, that is, it makes DNA and incorporates it into the infected person's cells. This enables HIV to lie dormant in the cells, away from immune surveillance.

When HIV makes DNA, it interacts with PQBP1 in the dendritic cells, triggering the immune response.

Shane Crotty, a vaccine researcher at La Jolla Institute of Allergy & Immunology, said he liked the study.

"I think it's really neat. It made me smile," Crotty said. "I think it's one of those stories that tells us we still have a lot to learn about the immune system," Crotty said.

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