Nov. 27, 2000 BOSTON - With sinister efficiency, retroviruses such as HIV use only a small portion of their genetic programming to steal away from the cell where they were born and infect other cells. A study published this week by scientists at Dana-Farber Cancer Institute provides new details of how retroviruses make their escape and cloak themselves in the cell's membrane to avoid attack from the body's immune system.
The study, published in the November 21 issue of the Proceedings of the National Academy of Sciences, is one of three in the journal to focus on the mechanics of viral departure from cells - research that may one day lead to new techniques for arresting the process and preventing the spread of viral infection within the body.
"The last stages of the formation of viruses within cells and the process by which viruses leave cells are among the least understood aspects of the viral life cycle," says senior author Heinrich Göttlinger, M.D., of Dana-Farber and Harvard Medical School. "Our research sheds light on previously unknown aspects of this process and on the mechanisms that cause a virus to assemble in the first place."
The Dana-Farber study spotlights the function of ubiquitins, which help viruses break free from the cells where they were born, and on a viral segment known as the "late domain," which is in a protein called Gag. The domain, as its name suggests, comes into play late in the process by which viruses are assembled inside cells, just before they leave to infect other cells.
The process works like this: After infecting a cell, a virus takes over a cell's reproductive machinery to produce thousands of copies of itself. The not-yet-fully-assembled viruses - really just packets of RNA at this point - congregate inside the cell membrane like protesters pressing against a police barricade. The cell membrane begins to bulge and eventually forms a "bubble" that seals the viral RNA off from the rest of the cell (see accompanying illustration). Thousands of newborn viruses now cling to the outside of the membrane, waiting for one final step to cut them loose and send them on their way to other cells.
Ten years ago, Göttlinger and his colleagues at Dana-Farber discovered that a strain of HIV that lacks the late domain was unable to break free of the membrane - remaining attached and posing no threat to the rest of the body. The new study fills in some of the gaps in scientists' understanding of how the late domain functions and how it serves as a passport through the cell's skin.
Small as the late domain is within Gag, the domain's essential core - the part that enables it to function - often consists of only a handful of molecules, primarily amino acids known as prolines. Researchers have found that all retroviruses, not just HIV, have late domains, as do a variety of other viruses.
"These findings suggest that many viruses use the same or similar mechanisms to cut themselves loose from the cell membrane," Göttlinger says. "The discovery of the proline-rich sections of the late domain enabled us to focus on precisely these areas in studying how the domain functions." The researchers hypothesized that the late domain serves as a target for cell proteins that help the virus break free from the cell membrane. Their research shows this to be precisely the case.
The possibility of interrupting the budding process marks the significance of this recently published research. Working independently, scientists at Dana-Farber Cancer Institute, Penn State's College of Medicine and The National Institute of Allergies and Infectious Diseases (NIAID) of the National Institutes of Health, published complementary papers on the role of the cellular ubiquitination machinery in late steps of retrovirus budding.
The data show the functional connection between ubiquitin and Gag (Penn State), the recruitment of ubiquitin ligase, which encourages the virus budding (Dana-Farber) and the maturation of Gag, the final stage in which the virus becomes infectious (NIAID). Each paper presents a slightly different view of these connections.
"We discovered that the late domain attracts the cellular 'machinery' that causes proteins called ubiquitins to attach to Gag," Göttlinger says. "This binding enables the 'buds' of virus to leave the cell membrane and spread to other cells. The fact that retroviruses can use this mechanism to escape the cell without destroying it may be a significant advantage to their survival and spread."
Researchers don't yet know the identity of the machinery that binds the ubiquitins to Gag, nor do they know if the machinery interacts with more than one site on Gag. These questions are the focus of Göttlinger's lab's current study.
"The more details we learn about the process of viral budding, the better position we will be in, ultimately, to design therapies that can stop it in its tracks," Göttlinger says. "It represents a portion of the virus's life cycle that may leave the virus vulnerable to attack by medication or other therapy."
Dr. Göttlinger's work emanated from Dana-Farber Cancer Institute's Center for Aids Research--one of only 18 such centers in the United States. Dana-Farber Cancer Institute is among the nation's leading cancer research and care centers.
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