Proteins that help clean and organize the inside of certain T cells may assist HIV in spreading through the body, scientists from the National Institute of Allergy and Infectious Diseases (NIAID) report in the November 21 issue of the Proceedings of the National Academy of Sciences. The new report, which complements studies by two other laboratories, is the first to implicate a collection of housekeeping proteins, collectively called the ubiquitin-proteasome system, in spreading HIV from one cell to another.
"We know more about HIV than about any other virus, and yet it continues to reveal new secrets," states Anthony S. Fauci, M.D., director of NIAID. "This discovery provides another example of how HIV manipulates T cells for its own survival and sheds light on a poorly understood type of virus-cell interaction."
The proteasome is the cell's garbage disposal, collecting and destroying old or damaged proteins, or proteins that are no longer needed. A molecule called ubiquitin is the chemical flag that often determines a protein's fate; a single ubiquitin molecule flag helps regulate a protein's function, whereas multiple flags target the protein for destruction.
Ulrich Schubert, Ph.D., a visiting scientist in NIAID's Laboratory of Viral Diseases, led a team of researchers from several institutions in a study of the ubiquitin-proteasome system in HIV-infected CD4+ T cells, the major target of the virus. The researchers used chemicals to shut down this system, and then compared the behavior of HIV in treated and untreated cells.
The results showed significant changes in the ability of the virus to exit CD4+ T cells and infect neighboring cells. When HIV particles exit the cell in a process called budding, they normally wrap themselves in a piece of the cell's membrane as they leave. The departing viruses therefore have an envelope that can fuse with the membranes of nearby cells, allowing the virus to enter. When Dr. Schubert and co-workers chemically blocked the proteasome, however, many of the budding virus particles failed to pull their stolen membrane loose as they tried to exit the cell, leaving them trapped on the surface. Furthermore, those viruses that did manage to escape often failed to mature properly, reducing their ability to infect other cells.
"Besides being able to spread by direct cell contact, HIV can bud from one cell if it is going to infect others, and by blocking the ubiquitin-proteasome system we partially prevent that from happening," explains Dr. Schubert, who also maintains a laboratory at Heinrich-Pette Institut in Hamburg, Germany. "Of the viruses that do manage to escape the surface, many fail to complete the biochemical changes that usually occur after they leave the cell, making them less able to infect new cells."
Deficiencies in both viral budding and maturation have been linked to so-called late assembly, or L, domain genes of HIV. When the scientists looked at the proteasome-blocked cells, some of the L-domain proteins lacked ubiquitin. One possible explanation for this discovery is that L-domain proteins might not assemble properly if they don't have their single ubiquitin molecule, a possibility that Dr. Schubert is currently investigating.
The two other PNAS reports, consistent with Dr. Schubert's work, take steps to explain how the ubiquitin-proteasome system affects HIV. In research partly funded by NIAID, Bettina Strack, Ph.D., and Heinrich Göttlinger, Ph.D., of Dana-Farber Cancer Institute and Harvard Medical School, led a research team that studied L-domain function in HIV and other viruses. They discovered that L domains use the ubiquitin-proteasome system to help mediate virus release. Their studies support a role for interactions between this system and L domains in a diverse group of viruses.
In the third paper, graduate student Akash Patnaik and John Wills, Ph.D., from Pennsylvania State University College of Medicine, independently showed that budding of a cancer-causing retrovirus called Rous sarcoma virus is deficient in cells with low ubiquitin levels. The researchers also used electron microscopy to study why the virus particles cannot bud from the cell. They report that ubiquitin is an important part of the budding machinery, required for the virus to release itself from the cell surface.
In combination, these three new studies demonstrate a role for the ubiquitin-proteasome system in the release of several viruses from the membrane, and opens new avenues of research on HIV and other viruses. The scientists will now focus on better understanding the precise mechanism by which ubiquitin and the proteasome regulate viral budding and maturation.
Jonathan Yewdell, M.D., Ph.D., chief of the laboratory section in which Dr. Schubert's research took place, cautions that developing an anti-HIV drug that blocks the proteasome is unlikely. "The proteasome is important for almost all cellular functions, so such drugs would be toxic to the cell. Even our studies have a narrow time window when we can study the cells before they die." Drs. Schubert and Yewdell agree, however, that providing a thorough understanding of the interactions between HIV proteins and the ubiquitin-proteasome system may in the future reveal new ways to attack the virus.
Materials provided by NIH/National Institute Of Allergy And Infectious Diseases. Note: Content may be edited for style and length.
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