A multi-institutional research center run by the University of Utah Health that studies the inner workings and vulnerabilities of HIV, the human immunodeficiency virus that causes AIDS, recently received a $28 million grant renewal. over five years from the National Institutes of Health.
Since its creation in 2007, the CHEETAH Center for Structural Biology of HIV Infection Restriction and Viral Dynamics has published over 300 research articles that have led to a better understanding of HIV and its potential treatments.
Wesley Sunquist, director of the center, professor and chair of the department of biochemistry at U of U Health, leads 20 research teams from 12 institutions. With the renewal of the grant, researchers will focus on:
- Determine how HIV infects cells,
- Understand how host cells defend themselves against the virus,
- Analyze how the virus becomes dormant and rebounds, and
- Develop next-generation tools and methodologies to better understand the structure and mechanisms of HIV.
“The exceptional science emerging from this program is changing the understanding of HIV/AIDS, other viral diseases and cell biology, enabling the development of new therapies such as lenacapavir and D-peptide inhibitors,” says Rachel Hesseassociate vice president for research at U of U Health, referring to two experimental drugs with roots in CHEETAH.
From Deep Understanding to Experimental Drugs
Just half a century ago, HIV infection almost inevitably led to serious illness and death. Today’s antiretroviral therapies can suppress the virus and prevent symptoms, but improvements are still needed. If these drugs are not taken daily, the virus can rebound and develop drug resistance. Medications can also cause harsh side effects. The foundations for two new experimental drugs that could help circumvent these problems are based on years of research by CHEETAH scientists.
Sundquist Research, Christopher Hill, distinguished professor of biochemistry at U of U Health and other CHEETAH Center labs on the HIV capsid – a structure they found vital to different stages of the HIV life cycle – laid the groundwork that has leads the pharmaceutical company Gilead Sciences to identify the capsid inhibitor, lenacapavir. This investigational drug is currently in phase 3 clinical trials and is already very promising as a powerful, long-acting treatment.
By taking a different approach, Michael KayCHEETAH researcher and professor of biochemistry, and Debra Eckertassistant research professor of biochemistry, used synthetic chemistry to design a D-peptide inhibitor called CPT31 that blocks the HIV infection machinery. The molecule is now in phase 1 clinical trials sponsored by Navigen, Inc.
“People often forget that drug development is based on basic research,” says Sundquist. “These are two more instances where this has happened, and it’s very satisfying.”
Learning the lessons of HIV
CHEETAH continues to bring an understanding of HIV, related viruses, and host biology in new directions through collaborations among its scientists, who come from a variety of disciplines. “The CHEETAH Center does exciting, interdisciplinary science in a collaborative environment that allows us to do projects that otherwise wouldn’t be possible in a single lab,” says Pamela Bjorkman, professor of biology and bioengineering at Caltech.
Nels Elde, a professor of human genetics at U of U Health, looks to evolution for inspiration, noting that many animals are not as susceptible as humans to illnesses caused by HIV. He is collaborating with other CHEETAH scientists to determine whether a gene found in mice and squirrel monkeys that prevents HIV from leaving cells after replication could become the basis of a new type of antiviral.
“Nature has apparently had countless billions of experiments that have brought us to where we are today,” says Elde. “Can we learn from what happened and borrow and deploy them in useful ways?”
In contrast, Owen Pornillos, a CHEETAH researcher at the University of Virginia who earned his Ph.D. from the U, takes advantage of his expertise in biochemistry to take a different approach. In a collaborative project with several members of the CHEETAH Center, he removes the virus from the host cell’s complex environment and brings it to the test tube. By adding a few specific ingredients at a time, the team identifies key virus and host cell components that are essential in the early stages of viral infection and replication. Combining this approach with new microscope technologies allows them to visualize these steps with unprecedented clarity.
“CHEETAH is committed to scientific excellence and is always planning where we envision the field five years from now,” Pornillos said. “It’s exciting to be a part of it.”
These diverse tactics provide valuable insights into virology and biology, and uncover targets for new types of therapeutic interventions.