HIV, the virus that causes AIDS, is a master of molecular disguise, mutating so frequently that existing drugs eventually become unable to halt its replication. Michael F. Summers is unraveling the internal architecture of HIV, striving to understand how it and other retroviruses assemble, and how they package their genetic material so that they can infect other cells. Relying on nuclear magnetic resonance (NMR) spectroscopy, he and his team have solved the three-dimensional structures of three proteins that make up the virus, and they are now using this information to decipher the way HIV proteins interact with each other and with the cells they infect. Ultimately his studies could aid in the design of new treatment approaches for AIDS and other human diseases caused by retroviruses.
Despite the complex nature of this work, Summers has made a point of assigning key roles on his research team to his students—many of them undergraduates who also happen to be top minority students. He is deeply committed to nurturing aspiring biomedical scientists and to making opportunities for his young students to have hands-on research experience. "Young people need to have experiences that excite them and motivate their interest in science," Summers says. "Making our laboratories available to bright young students is important for developing the next generation of scientists, and can be personally very rewarding."
When Summers started his own lab at the University of Maryland, Baltimore County, he was intrigued by a scientific controversy over whether the nucleocapsid protein surrounding HIV's viral core requires zinc to fold and function properly. Summers' training made him well suited to resolve the dispute. As a Ph.D. student, he investigated the role of metals in biology, and as a postdoctoral fellow at the National Institutes of Health, his interest was NMR spectroscopy, a technique that helps scientists construct a picture of a protein by supplying information about the relative distance between individual atoms. Using NMR, Summers found that the nucleocapsid protein binds zinc tightly, a union that induces the formation of a stable region called a "zinc knuckle." He also showed that zinc knuckles are an important component of mature viruses, which are those capable of infecting other cells. "Those early experiments stimulated my interest in understanding the structures and functions of other components of HIV and retroviruses in general," Summers says.
A major focus of Summers' research is HIV's Gag protein complex—a grouping of the nucleocapsid and two other proteins. After the genetic material of the virus is copied, Gag controls the assembly of HIV by bringing together all the components needed to form a fully infectious virus. In a series of studies beginning in the early 1990s, Summers' lab deciphered the structures of the proteins that make up the Gag complex and demonstrated the key role of the nuclecapsid in viral assembly. Like all other retroviruses, HIV stores its genetic contents in the form of RNA. The nucleocapsid protein recognizes and binds to the RNA, then packages it for delivery into the core of newly formed viral particles that bud off to infect other cells. Summers and his colleagues used NMR to determine the structure of the nucleocapsid when it is tethered to RNA, finding that the protein recognizes and grasps specific sites on the RNA molecule using two zinc knuckles. This research also suggests that the zinc knuckles are a promising drug target because they are resistant to mutations commonly found in other regions of the virus, Summers says.
In recent years, Summers has uncovered a molecular switching mechanism that plays an important role in HIV infection. When the switch is "on" the Gag protein complex binds tightly to the membrane of an infected cell so that the virus can assemble. After the virus forms and buds off, the switch turns "off." Only then is Gag cleaved into its component parts, a process that transforms newly formed but immature HIV into a mature virus that is capable of infecting other cells. Summers has also identified a new class of compounds that inhibit a key protein involved in the transformation of HIV into its mature form.
Summers' mentoring has earned him as much praise in some circles as his achievements in the laboratory. More than 120 undergraduates have trained in his lab, about half of them African Americans, and most go on to highly regarded PhD or MD-PhD programs. "While I am very proud of our research, I think it is the work I've done with the students that brings me the greatest personal satisfaction and may, in the end, be of greatest importance," he says.
Dr. Summers is also Professor of Chemistry and Biochemistry at the University of Maryland, Baltimore County, and Adjunct Professor of Biological Chemistry at the University of Maryland School of Medicine in Baltimore.
RESEARCH ABSTRACT SUMMARY:
Michael Summers is interested in the application of nuclear magnetic resonance to studies of retrovirus structure and function.
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