Molecular Traffic Signal Could Be New HIV Drug Target
A single HIV protein acts as a molecular traffic signal to regulate crucial steps in the virus' life cycle, a new study has found. The discovery of these previously unrecognized stop-and-go functions provides new targets for creating molecular gridlock and halting virus growth. A research team led by Michael R. Green, M.D., Ph.D., and Mario Stevenson, Ph.D., of the University of Massachusetts Medical Center in Worcester, reports the findings in the Dec. 9, 1999 issue of Nature.
"This study helps fill in a missing piece of the HIV reproduction process," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which funded the study. "The findings suggest we may be able to devise therapies that subvert the order and timing of cellular events necessary for HIV replication."
By systematically analyzing the properties of normal and mutant forms of HIV, Drs. Green, Stevenson and their colleagues found that a molecule known as HIV matrix protein, an important building block within HIV's core, controls two opposing functions. Each function comes into play during a different stage in the HIV infection cycle.
For HIV to reproduce inside human cells, it must first invade the nucleus and commandeer the cell's genetic machinery. "Early after HIV infection, matrix protein helps import HIV genetic material into the nucleus of the infected cell," says Dr. Green. Once inside the nucleus, HIV co-opts the genetic machinery to churn out copies of the virus' genetic material, called RNA. That viral RNA then forms the genetic blueprints from which new HIV proteins are constructed.
Later in the infection cycle, the matrix protein reverses the flow of traffic and directs new HIV proteins away from the nucleus and into the surrounding cell cytoplasm where new viruses are assembled and packaged.
"How matrix protein suddenly reverses course has been a mystery," says Dr. Green. "Our study shows that the nuclear export signal kicks in late after infection."
"These data confirm what other studies have suggested - that matrix protein helps localize HIV genetic material to the cell nucleus so that integration and transcription can take place," notes Nava Sarver, Ph.D., chief of the targeted interventions branch in NIAID's Division of AIDS. "The evidence that the matrix protein also has a nuclear export activity required for viral replication is exciting new information."
"The opposing functions of the HIV matrix protein represent two new discrete targets for anti-HIV drugs," adds Dr. Sarver. "Drugs designed to block either the import or export signals can undermine the carefully orchestrated course of events during HIV replication, and could shut down the growth of the virus."
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services. The Howard Hughes Medical Institute also provided support for this study.
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S Dupont, N Sharova, C DeHoratius, C-MA Virbasius, X Zhu, AG Bukrinskaya, M Stevenson and MR Green. A novel nuclear export activity in HIV-1 matrix protein required for viral replication. Nature 402:681-85 (1999).