NIH grant awarded to investigate how immune system can banish HIV

Weill Cornell Medicine has received $4.2 million to study how the immune system in some people infected with HIV can keep the virus under control, which could lead to novel therapeutic strategies for thwarting or eliminating HIV.

Brad Jones, associate professor of immunology in medicine in the Division of Infectious Diseasesat Weill Cornell Medicine, was awarded a MERIT grant from the National Institute for Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).

The "Method for Extending Research in Time" (MERIT) grant provides outstanding investigators longer-term support for high-risk, high-reward experiments that could lead to major breakthroughs. Fewer than 5% of funded NIH investigators are selected to receive the prestigious award.

"It's exciting and rewarding to have the importance of the work recognized in this way," Jones said. "Not only for me but for the students and technicians and everyone on the team who has been working really hard on the project."

The human immunodeficiency virus (HIV) is elusive and resilient, evading the immune system by incorporating its genetic material into the host's DNA - hiding in plain sight inside infected cells that persist despite treatment. Although antiretroviral therapy can reduce HIV in the blood to an undetectable level, these dormant reservoirs continue to survive, ready to re-emerge if therapy is interrupted.

To understand how the virus persists in the body, Jones and his group developed a "patient-derived xenograft" (PDX) mouse modelthat can replicate the immune system of those rare individuals, dubbed elite controllers, who keep the virus in check - even in the absence of antiretroviral medications.

"What's remarkable is the degree of immune control of HIV that we see in the person is born out in the model," Jones said. Both show that much of the HIV hiding in the cells of elite controllers has been banished to gene-poor deserts in the host genome from which the virus is unlikely to be reactivated.

Jones and his team will use the PDX model to explore whether and how immune cells called killer T cells from elite controllers pressure the virus to bury itself in remote locations. They can also assess whether boosting the activity of these killer T cells enhances HIV exile.

His lab will also explore whether HIV can, in some cases, selectively integrate itself into genes that promote cell survival - giving the virus more time to replicate and spread.

"If that's the case, we have an even tougher problem to solve in our search for a cure," Jones said. Determining the types of genes that HIV favors could suggest potential therapeutic targets and different treatment approaches. For example, if HIV is protecting the cells it infects by inhibiting apoptosis (cell death), treatment with drugs that promote cell death could diminish HIV's advantage and empower the immune system to regain the upper hand.

Building a map of the sites where the virus integrates into the host genome could also allow researchers to evaluate the effectiveness of a therapy based on how well it exiles HIV. "If we can sequester enough of the remaining virus that it's not going to come back in that person's lifetime, we'll be that much closer to a cure," Jones said.

Karen Hopkin is a freelance writer for Weill Cornell Medicine.

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