Molecules seen binding to HIV-1's protective capsule, blocking infection

December 30, 2014

SAN ANTONIO (Dec. 30, 2014) -- Imagine a suitcase on a bumpy ride. With enough jostling it opens, spilling clothes everywhere. Similarly awkward, the suitcase locks may jam and not open at the destination.

This analogy illustrates the importance of the protective capsule, called the capsid, which surrounds the HIV-1 genome. (HIV is short for human immunodeficiency virus.) The capsid has to disassemble once the virus enters the cell, releasing its disease-causing cargo at precisely the right time and place.

"It's still a matter of debate at what point the capsid falls apart in HIV-1 infection of cells," said Dmitri Ivanov, Ph.D., assistant professor of biochemistry in the School of Medicine at The University of Texas Health Science Center at San Antonio. Dr. Ivanov is a senior author on a study, published Dec. 15 in Proceedings of the National Academy of Sciences, that offers clues about HIV-1 capsid disassembly.

The paper shows how an HIV-1 inhibitor called PF74 and a host protein called CPSF6 bind to a small pocket on the surface of the capsid and prevent it from disassembling. The suitcase, if you will, is locked. Viral information is kept inside.

"We think that this process can be targeted for therapeutic purposes in HIV-1 infections," Dr. Ivanov said.

In part of the study, researchers used X-ray crystallography at the UT Health Science Center to visualize the three-dimensional structure of the CPSF6 protein bound to the HIV-1 capsid.

"Seeing molecules in 3-D is illuminating; it tells us something about their function," Dr. Ivanov said. "We now know how PF74 and CPSF6 interact with the adjacent building blocks of the HIV-1 capsid, thus stabilizing the entire capsid structure. It tells us that these molecules bind to the capsid before disassembly, blocking viral replication."
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Structural basis of HIV-1 capsid recognition by PF74 and CPSF6

Akash Bhattacharya a, Steven L. Alam b, Thomas Fricke c, Kaneil Zadrozny d, Jaroslaw Sedzicki d, Alexander B. Taylor a, Borries Demeler a, Owen Pornillos d,e, Barbie K. Ganser-Pornillos d, Felipe Diaz-Griffero c, Dmitri N. Ivanov a,1, and Mark Yeagerd e,f,g,1

a Department of Biochemistry and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; b Department of Biochemistry, University of Utah, Salt Lake City, UT 84112; c Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and d Department of Molecular Physiology and Biological Physics, e Center for Membrane Biology, f Cardiovascular Research Center, and g Division of Cardiovascular Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908

1 To whom correspondence may be addressed. Email: ivanov@uthscsa.edu or yeager@virginia.edu.

This article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1419945112/-/DCSupplemental.

For current news from the UT Health Science Center San Antonio, please visit our news release website, like us on Facebook or follow us on Twitter.

The University of Texas Health Science Center at San Antonio, one of the country's leading health sciences universities, ranks in the top 13 percent of academic institutions receiving National Institutes of Health (NIH) funding. The university's schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 29,000 graduates. The $787.7 million operating budget supports eight campuses in San Antonio, Laredo, Harlingen and Edinburg. For more information on the many ways "We make lives better," visit http://www.uthscsa.edu.

University of Texas Health Science Center at San Antonio

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