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Ohio State Researchers Uncover New Approaches for Combating HIV
The AIDS epidemic remains a key global health issue, with approximately 36 million people worldwide currently infected with human immunodeficiency virus (HIV), the causative agent of AIDS. Use of antiretroviral therapy (ART) have enabled healthcare professionals to transform a once deadly infection into a chronic illness for patients with access to them. Yet being an ART patient means life-long treatments and the threat of increasingly resistant HIV-1 strains that compromise drug therapy. Mamuka Kvaratskhelia, PhD, Kimberly Professor at the Ohio State College of Pharmacy and Center for Retrovirus Research, and his research group have uncovered a new mechanism for halting the spread of infectious viruses that could pave the way for therapies to combat emerging HIV-1 strains resistant to currently available treatments. These findings are reported in the August 25 issue of Cell, the eminent life sciences journal.
Kvaratskhelia and his team sought to alter the structure of integrase, a key HIV-1 protein, using small molecules called allosteric integrase inhibitors, or ALLINIs. These studies have resulted in discovery of a new and unexpected role for integrase in HIV-1 biology and revealed the mechanism that causes ALLINIs to impair HIV-1 replication.
HIV-1 life cycle is broadly divided into two phases: the early phase, when the virus invades human cells to establish the infection; and the late phase, when infected cells make new virus particles that infect other cells. Historically, it was thought that integrase acts only during the early phase of HIV-1 infection by integrating the viral copy DNA into the human genome. Yet in this study Kvaratskhelia’s team, in collaboration with Sebla B. Kutluay, PhD, Washington University School of Medicine and Paul D. Bieniasz, PhD, The Rockefeller University, have found that integrase is also essential for the late phase where it ensures that viral RNA, which is the genetic code of HIV-1, is correctly positioned within the infectious virus particles.
Furthermore, these investigators have found that ALLINIs altered the structure of integrase and impaired its ability to bind the viral RNA, thus yielding non-infectious particles. The outer shells of the newly formed particles were normal, but the internal components were profoundly altered with the viral RNA genome being misplaced.
“Normally, scientists first try to understand biological processes for how viruses replicate and then drugs are developed to block specific biochemical steps in the virus life cycle,” said Kvaratskhelia. “In this case, ALLINIs helped us to uncover a previously unknown biological role of integrase for making infectious virus particles.” Kvaratskhelia’s team is currently working with medicinal chemists at Ohio State to develop ALLINIs that can be used to treat AIDS patients.
Other authors of the study include Jacques J. Kessl, Dana Townsend, Stephanie Rebensburg, Alison Slaughter, Ross C. Larue, Nikoloz Shkriabai, Nordine Bakouche and James R. Fuchs. These studies where supported by National Institutes of Health grants R01AI062520, P50GM103368, and R01AI110310 awarded to Kvaratskhelia