SAN FRANCISCO, Nov. 1 (UPI) -- Researchers have found clues that
point to the extraordinary, terrorist-like power of a single
protein to promote HIV infection and progression.
It appears that in an "absolutely amazing" process, the protein
forces the membrane around the cell nucleus -- the nuclear
envelope -- to rupture, spilling its cargo in a mixture deadly to
disease-fighting warriors of the immune system, they said in the
The gene, called Vpr, empowers the human immunodeficiency virus
to halt the proliferation of vital T-cells -- key components of
the body's defense against disease -- and spread unimpeded, said
the study authors from the University of California, San
Francisco, and Northwestern University in Evanston, Ill.
Such a profound effect from a single protein is "remarkable" and
carries significant implications for the development of a new
class of treatments, though these are still a long ways off,
scientists told United Press International.
Studies indicated Vpr shuts down dividing CD4+ T cells at a
strategic point in the cell cycle, allowing extended replication
of the AIDS virus, HIV. The details of this mechanism came to
light in a meticulously crafted study of cellular factories
producing the protein. Made possible with cutting-edge time lapse
video microscopy, the glimpse of the intriguing world of HIV
biology revealed startling images of rupture-prone protrusions on
the nuclear envelope.
In a unique process, Vpr causes the nuclear envelope to form
herniations that swell and shrink much like solar flares
radiating from the sun's surface, the investigators found. No
such system has been described for any other virus.
As the protrusions intermittently burst apart at the seams, the
nuclear contents and the cytoplasm from which they had been so
carefully guarded stream together in a lethal combination that
lays the groundwork for the viral takeover of the cell and,
eventually, of the entire immune system.
"It is absolutely amazing how the virus breaches the nuclear
envelope; it's like breaching the castle walls from the inside,"
senior study author Dr. Warner Greene, director of the UCSF
Gladstone Institute of Virology and Immunology, said in a
telephone interview from the O'Hare International Airport in
Chicago. "Everything can stream out of and in to the nucleus."
Vpr produces these life-changing alterations in nuclear
architecture by tampering with the highly ordered structure of a
family of proteins called the nuclear lamins. The lamins form a
supporting network of filaments that line the inner surface of
the nuclear envelope.
"In the presence of Vpr, the structure of the nuclear lamins
becomes disorganized," said lead author Carlos de Noronha,
research scientist at Gladstone.
"To us, the finding was certainly startling," said Greene, UCSF
professor of medicine, microbiology and immunology. "That HIV has
the capacity to alter in a dynamic way the structure of the
nuclear envelope and to compromise the very tightly regulated
central structure of nuclear proteins is a completely unexpected
property of the virus."
These changes combine to disable the cell from carrying out cell
division and other vital functions. Once it prevents the cell's
division, HIV is well on its way to conquering the hapless host.
Without cell division, virus production is stepped up multi-fold,
giving HIV unlimited possibilities to grow.
"Then HIV can infect more new target cells, leading to faster
spread of the infection," de Noronha explained.
"It is remarkable that a single protein, Vpr, can so profoundly
disrupt nuclear envelope structure," said Miriam Seura-Totten and
Katherine Wilson of Johns Hopkins University School of Medicine
in Baltimore, Md., who analyzed the findings in an accompanying
"These new findings reveal a previously unknown aspect of the HIV
virus life cycle, namely, how the virus enters the nucleus of
non-dividing cells, and suggest a possible new target for
inhibitory drugs: the virally encoded Vpr protein," Wilson,
associate professor of cell biology, told UPI. "Inhibitors that
block Vpr might reduce the rate at which the virus spreads to new
and especially non-dividing cells. Vpr was not previously
considered a target, because its function was not known."
The findings will have important implications for both scientists
and patients once the researchers figure out exactly which
nuclear protein or proteins the virus subverts to "blow the
hatch" on the nuclear envelope, Wilson said.
"The analogy with terrorism is obvious: the work described in the
Science paper shows that a small number of virally encoded Vpr
proteins can enter the nucleus and selectively destroy or
destabilize structures within the nucleus," Wilson said. "If Vpr
turns out to sabotage a nuclear protein that is essential for
life, this knowledge might not help much in terms of new drug
therapy. However, if Vpr sabotages a non-essential nuclear
protein, this might give researchers an additional new protein --
besides Vpr -- to target for anti-viral therapy."
"Viruses are masters of warfare and terrorism, who have copied or
subverted important cellular proteins, and then use these
proteins against the host cell," Wilson added. "As a scientist
who studies nuclear structure, I hope that further study of Vpr's
effect on the nucleus will have a scientific 'silver lining,' by
improving our understanding of nuclear structure."
The findings would not have been possible without Digital Age
"We would have not detected these remarkable changes in nuclear
envelope structure induced by Vpr if we had not turned to time
lapse video microscopy that permits analysis of a single cell
over time," Greene said.
The tool provides a very close-up view of living cells and key
molecules of interest, which, tagged with fluorescent proteins
with a tell-tale glow, can be easily followed as they move around
"These experiments have provided us with an entirely new
perspective on how HIV impairs the progression of cells through
the normal cell cycle," Greene said.
Hopefully, the newfound understanding will lead to novel
treatments for the arsenal of aging therapy strategies is wearing
thin and stands in need of restocking with fresh supplies,
"Already, we're seeing the emergence of viruses that are
resistant to multiple drugs that we have. That says we need new
classes of drugs, new approaches, new targets of the retroviral
life cycle," Greene said. "I'm not sure at this point exactly
where the finding will lead us, but I do know the more we
understand the basic principles of how HIV takes over CD4+
T-cells, the better position we will be in to interrupt that