Map of herpes virus protein suggests a new drug therapy

ScienceDaily (July 8, 2010) — The mechanism by which a herpes virus invades cells has remained a mystery to scientists seeking to thwart this family of viruses. New research funded by the National Institutes of Health and published online in advance of print in Nature Structural & Molecular Biology reveals the unusual structure of the protein complex that allows a herpes virus to invade cells. This detailed map of a key piece of the herpes virus "cell-entry machinery" gives scientists a new target for antiviral drugs.

"Most viruses need cell-entry proteins called fusogens in order to invade cells. We have known that the herpes virus fusogen does not act alone and that a complex of two other viral cell-entry proteins is always required. We expected that this complex was also a fusogen, but after determining the structure of this key protein complex, we found that it does not resemble other known fusogens," said senior author Ekaterina Heldwein, PhD, assistant professor in the molecular biology and microbiology department at Tufts University School of Medicine.

"This unexpected result leads us to believe that this protein complex is not a fusogen itself but that it regulates the fusogen. We also found that certain antibodies interfere with the ability of this protein complex to bind to the fusogen, evidence that antiviral drugs that target this interaction could prevent viral infection," Heldwein continued. Heldwein is also a member of the biochemistry and molecular microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"Katya Heldwein's work has resulted in a map of the protein complex needed to trigger herpes virus infection. The NIH Director's New Innovator Awards are designed to support such breakthroughs. This research not only adds to what we know about how herpes viruses infect mammalian cells, but also sets the stage for new therapeutics that restrict herpes virus's access to the cell," said Jeremy M. Berg, PhD, director of the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health.

"We hope that determining the structure of this essential piece of the herpes virus cell-entry machinery will help us answer some of the many questions about how herpes virus initiates infection. Knowing the structures of cell-entry proteins will help us find the best strategy for interfering with this pervasive family of viruses," said first author Tirumala K. Chowdary, PhD, a postdoctoral associate in the department of molecular biology and microbiology at TUSM and member of Heldwein's lab.

Currently, there is no cure for herpes viruses. Upon infection, the viruses remain in the body for life and can stay inactive for long periods of time. When active, however, different herpes viruses can cause cold sores, blindness, encephalitis, or cancers. More than half of Americans are infected with herpes simplex virus type 1 (HSV-1), which causes cold sores, by the time they reach their 20s. Currently, about one in six Americans is infected with herpes simplex virus type 2 (HSV-2), the virus responsible for genital herpes. Complications of HSV-2, a sexually-transmitted disease, include recurrent painful genital sores, psychological distress, and, if transmitted from mother to child, potentially fatal infections in newborn infants.

Heldwein teamed up with colleagues at University of Pennsylvania and used x-ray crystallography along with cell microscopy techniques to study the structure and function of this cell-entry protein complex in HSV-2. Heldwein is currently developing a molecular movie that illustrates how herpes virus enters the cell.

Additional authors are Tina Cairns, PhD, a research specialist; Doina Atanasiu, a research associate; and Gary Cohen, PhD, professor and chair, all in the department of microbiology at the University of Pennsylvania School of Dental Medicine; and Roselyn Eisenberg, PhD, professor in the department of microbiology at the University of Pennsylvania School of Veterinary Medicine.

This work was funded by the Office of the Director of the National Institutes of Health, through a New Innovator Award in 2007 to Ekaterina Heldwein. The New Innovator Awards, part of the NIH Roadmap for Medical Research initiative, are awarded to support early-career scientists who take innovative -- and potentially transformative -- approaches to major challenges in biomedical research. The work was also funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Pew Scholar Program in Biomedical Sciences.

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The above story is reprinted from materials provided by Tufts University, Health Sciences.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Tirumala K Chowdary, Tina M Cairns, Doina Atanasiu, Gary H Cohen, Roselyn J Eisenberg, Ekaterina E Heldwein. Crystal structure of the conserved herpesvirus fusion regulator complex gH-gL. Nature Structural & Molecular Biology, 2010; DOI: 10.1038/nsmb.1837

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Cellular protein hobbles HIV-1

ScienceDaily (Dec. 13, 2010) — A cellular protein called BST-2 had already been known to interfere with the spread of human immunodeficiency virus type 1 (HIV-1), by inhibiting the release of its progeny particles from infected cells. Now a team from McGill University, Montreal, shows that in addition, each progeny virion's ability to cause infection is severely impaired.

"BST-2 may exert a more potent inhibition effect on HIV-1 transmission than previously thought," says coauthor Chen Liang. The research is published in the December Journal of Virology.

BST-2 appears to attenuate infectivity of progeny particles by interfering with their maturation. Normally, during synthesis of new virus particles, a protein called PR55Gag is cleaved into three major structural proteins of HIV. "This cleavage process transforms HIV-1 from an immature and non-infectious virion into a mature and infectious virion," says Chen. The protease inhibitors, drugs given to AIDS patients to contain the disease, block this step. Similarly, BST-2 seems to interfere with this step, because in the study, its presence was associated with accumulation of uncleaved Gag precursor and intermediate products. The mechanism of that interference has yet to be elucidated.

BST-2 (bone marrow stromal cell antigen-2), also known as tetherin, is a cellular protein which has been shown to restrict production of enveloped viruses besides HIV-1, including HIV-2, simian immunodeficiency virus, Kaposi's sarcoma herpes virus, Lassa virus, Marburg virus, and Ebola virus. It interferes with release of new virus particles by anchoring one end of itself in the plasma membrane of the infected cell while the other end becomes inserted into the viral envelope.

Different viruses have evolved various countermeasures. For example, in the case of HIV-1, the viral protein Vpu downregulates BST-2 from the cell surface, removing it from virus budding sites.

"The antiviral function of BST-2 has been extensively studied by a number of groups besides ours," says Chen. "Our hope is that the results of all of these studies can eventually be used to develop a BST-2 based anti-HIV-1 therapy."

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The above story is reprinted from materials provided by American Society for Microbiology.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

J. Zhang, C. Liang. BST-2 Diminishes HIV-1 Infectivity. Journal of Virology, 2010; 84 (23): 12336 DOI: 10.1128/JVI.01228-10

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Cellular protein hobbles HIV-1

ScienceDaily (Nov. 16, 2010) — A cellular protein called BST-2 had already been known to interfere with the spread of human immunodeficiency virus type 1 (HIV-1), by inhibiting the release of its progeny particles from infected cells. Now a team from McGill University, Montreal, shows that in addition, each progeny virion's ability to cause infection is severely impaired.

"BST-2 may exert a more potent inhibition effect on HIV-1 transmission than previously thought," says coauthor Chen Liang. The research is published in the December Journal of Virology.

BST-2 appears to attenuate infectivity of progeny particles by interfering with their maturation. Normally, during synthesis of new virus particles, a protein called PR55Gag is cleaved into three major structural proteins of HIV. "This cleavage process transforms HIV-1 from an immature and non-infectious virion into a mature and infectious virion," says Chen. The protease inhibitors, drugs given to AIDS patients to contain the disease, block this step. Similarly, BST-2 seems to interfere with this step, because in the study, its presence was associated with accumulation of uncleaved Gag precursor and intermediate products. The mechanism of that interference has yet to be elucidated.

BST-2 (bone marrow stromal cell antigen-2), also known as tetherin, is a cellular protein which has been shown to restrict production of enveloped viruses besides HIV-1, including HIV-2, simian immunodeficiency virus, Kaposi's sarcoma herpes virus, Lassa virus, Marburg virus, and Ebola virus. It interferes with release of new virus particles by anchoring one end of itself in the plasma membrane of the infected cell while the other end becomes inserted into the viral envelope.

Different viruses have evolved various countermeasures. For example, in the case of HIV-1, the viral protein Vpu downregulates BST-2 from the cell surface, removing it from virus budding sites.

"The antiviral function of BST-2 has been extensively studied by a number of groups besides ours," says Chen. "Our hope is that the results of all of these studies can eventually be used to develop a BST-2 based anti-HIV-1 therapy."

Share this story on Facebook, Twitter, and Google:

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Story Source:

The above story is reprinted from materials provided by American Society for Microbiology.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

J. Zhang, C. Liang. BST-2 Diminishes HIV-1 Infectivity. Journal of Virology, 2010; 84 (23): 12336 DOI: 10.1128/JVI.01228-10

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Map of herpes virus protein suggests a new drug therapy

ScienceDaily (July 6, 2010) — The mechanism by which a herpes virus invades cells has remained a mystery to scientists seeking to thwart this family of viruses. New research funded by the National Institutes of Health and published online in advance of print in Nature Structural & Molecular Biology reveals the unusual structure of the protein complex that allows a herpes virus to invade cells. This detailed map of a key piece of the herpes virus "cell-entry machinery" gives scientists a new target for antiviral drugs.

"Most viruses need cell-entry proteins called fusogens in order to invade cells. We have known that the herpes virus fusogen does not act alone and that a complex of two other viral cell-entry proteins is always required. We expected that this complex was also a fusogen, but after determining the structure of this key protein complex, we found that it does not resemble other known fusogens," said senior author Ekaterina Heldwein, PhD, assistant professor in the molecular biology and microbiology department at Tufts University School of Medicine.

"This unexpected result leads us to believe that this protein complex is not a fusogen itself but that it regulates the fusogen. We also found that certain antibodies interfere with the ability of this protein complex to bind to the fusogen, evidence that antiviral drugs that target this interaction could prevent viral infection," Heldwein continued. Heldwein is also a member of the biochemistry and molecular microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"Katya Heldwein's work has resulted in a map of the protein complex needed to trigger herpes virus infection. The NIH Director's New Innovator Awards are designed to support such breakthroughs. This research not only adds to what we know about how herpes viruses infect mammalian cells, but also sets the stage for new therapeutics that restrict herpes virus's access to the cell," said Jeremy M. Berg, PhD, director of the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health.

"We hope that determining the structure of this essential piece of the herpes virus cell-entry machinery will help us answer some of the many questions about how herpes virus initiates infection. Knowing the structures of cell-entry proteins will help us find the best strategy for interfering with this pervasive family of viruses," said first author Tirumala K. Chowdary, PhD, a postdoctoral associate in the department of molecular biology and microbiology at TUSM and member of Heldwein's lab.

Currently, there is no cure for herpes viruses. Upon infection, the viruses remain in the body for life and can stay inactive for long periods of time. When active, however, different herpes viruses can cause cold sores, blindness, encephalitis, or cancers. More than half of Americans are infected with herpes simplex virus type 1 (HSV-1), which causes cold sores, by the time they reach their 20s. Currently, about one in six Americans is infected with herpes simplex virus type 2 (HSV-2), the virus responsible for genital herpes. Complications of HSV-2, a sexually-transmitted disease, include recurrent painful genital sores, psychological distress, and, if transmitted from mother to child, potentially fatal infections in newborn infants.

Heldwein teamed up with colleagues at University of Pennsylvania and used x-ray crystallography along with cell microscopy techniques to study the structure and function of this cell-entry protein complex in HSV-2. Heldwein is currently developing a molecular movie that illustrates how herpes virus enters the cell.

Additional authors are Tina Cairns, PhD, a research specialist; Doina Atanasiu, a research associate; and Gary Cohen, PhD, professor and chair, all in the department of microbiology at the University of Pennsylvania School of Dental Medicine; and Roselyn Eisenberg, PhD, professor in the department of microbiology at the University of Pennsylvania School of Veterinary Medicine.

This work was funded by the Office of the Director of the National Institutes of Health, through a New Innovator Award in 2007 to Ekaterina Heldwein. The New Innovator Awards, part of the NIH Roadmap for Medical Research initiative, are awarded to support early-career scientists who take innovative -- and potentially transformative -- approaches to major challenges in biomedical research. The work was also funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Pew Scholar Program in Biomedical Sciences.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Tufts University, Health Sciences.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Tirumala K Chowdary, Tina M Cairns, Doina Atanasiu, Gary H Cohen, Roselyn J Eisenberg, Ekaterina E Heldwein. Crystal structure of the conserved herpesvirus fusion regulator complex gH-gL. Nature Structural & Molecular Biology, 2010; DOI: 10.1038/nsmb.1837

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here