NIH grant funds effort to target the root of HIV persistence

(Press-News.org) A multi-institutional team led by Weill Cornell Medicine has received a five-year, $14.9 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, to find ways to remove latent HIV from the cells of individuals with HIV. The team aims to use a personalized medicine approach to transform the management of HIV into effective cures.

Over 40 million people worldwide are living with HIV, according to the World Health Organization. People with HIV can manage their condition using antiretroviral drugs, which keep bloodstream levels of the virus near zero. But HIV persists in a latent form in some cells, and generally will reactivate, making the virus transmissible and ultimately causing AIDS, if antiretroviral therapy (ART) is stopped. HIV research now focuses to a great extent on the challenge posed by this latent viral reservoir.

The research program, called Innovative Strategies for Personalized Immunotherapies and Reservoir Eradication (INSPIRE), will be led by Dr. Brad Jones, associate professor of microbiology and immunology in the Division of Infectious Diseases at Weill Cornell Medicine.

The award is one of several large HIV-research grants for Weill Cornell Medicine in recent years—a team led by Dr. Jones received a $28.5 million NIH grant in 2021 for a broader, more basic research program on the principles of HIV latency.

“This new award validates our ongoing work and confirms that Weill Cornell Medicine has become a major global hub for HIV cure research,” Dr. Jones said.

HIV can insert its DNA into the genomes of the cells it infects, principally immune cells called CD4+ T cells. In some of these infected cells, HIV DNA is relatively silent, with little or no expression of viral proteins. These reservoir cells are rare, which further complicates the task of detecting them. The composition and activity levels of the viral reservoir also change over time and are apt to differ from one person to the next.

A key research aim for the INSPIRE project is to characterize these virus-harboring cells, essentially to determine the different types of HIV reservoir and their specific vulnerabilities to immune recognition and attack. This will be accomplished in part by studying a collection of reservoir cells that Dr. Jones and others on his team have already isolated from people with HIV.

Informed by improved knowledge about the HIV reservoir, the researchers will begin to investigate specific treatment strategies. One set of strategies, drawing upon the research team’s experience with cancer immunotherapies, will use tailored versions of a persons’ own T cells or related natural killer (NK) cells to target reservoir cells.

“Because the reservoir and immune responses vary among individuals, effective cures will likely require personalized approaches, much like cancer therapies,” said co-principal investigator Dr. Marina Caskey, professor of clinical investigation at The Rockefeller University and adjunct professor of medicine at Weill Cornell Medicine. “Working with collaborators at Weill Cornell, George Washington University, and the NIH, we aim to develop tailored immunotherapies—building on our experience with broadly neutralizing antibodies—to achieve durable, ART-free HIV remission.”

The team will experiment with engineering and reinfusing a persons’ B cells—which make antibodies—to create a sustained supply of broadly neutralizing antibodies against HIV, much as a vaccine would. Such antibodies can bind and neutralize a broad set of HIV strains, and are viewed as a promising weapon against HIV, although traditional vaccine approaches have not been successful in eliciting sufficient numbers of them.

“Having broadly neutralizing antibodies against HIV in the bloodstream long-term should effectively suppress the HIV reservoir, preventing rebound without the need for continued antiviral drug therapy,” Dr. Jones said. “It might even reduce the reservoir over time.”

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