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United Press International
Terrorist-like protein implicated in HIV
Lidia Wasowicz, UPI Senior Science Writer
November 1, 2001
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 journal Science.

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 Perspective commentary.

"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 technology.

"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 the cell.

"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, scientists said.

"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 process."

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