"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
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
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
"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
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
NIAID is a component of the National Institutes of Health (NIH). NIAID
supports basic and applied research to prevent, diagnose, and treat
infectious and immune-mediated illnesses, including HIV/AIDS and other
sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders,
asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at www.niaid.nih.gov.
2. B Strack, et al. A role for ubiquitin
ligase recruitment in retrovirus release. Proc Natl Acad Sci. (2000).
3. A Patnaik,
et al. Ubiquitin is part of the retrovirus budding machinery. Proc Natl Acad