Neurovirulent Strains of Alphavirus Induce Apoptosis in bcl-2-Expressing Cells: Role of a Single Amino Acid Change in the E2 Glycoprotein

The isolation and sequence comparison of avirulent and neurovirulent strains of polio virus, alpha virus, herpes virus, immunodeficiency virus, and other viruses have identified genetic changes that are required to cause disease in the nervous system. The molecular mechanisms by which these genetic...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-05, Vol.91 (11), p.5202-5206
Main Authors: Ubol, Sukathida, Tucker, Pamela C., Griffin, Diane E., Hardwick, J. Marie
Format: Article
Language:English
Subjects:
AIDS/HIV
alphavirus
Amino Acid Sequence
Amino acids
Animals
Apoptosis
B lymphocytes
Cell Line
Cell lines
Genetics
Glycoproteins
Humans
Killing
Medical research
Molecular Sequence Data
Mortality
Neurology
Neurons
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-bcl-2
Rats
Sindbis Virus
Sindbis Virus - genetics
Sindbis Virus - metabolism
Sindbis Virus - pathogenicity
Transfection
Tumor Cells, Cultured
Viral Envelope Proteins - metabolism
Virulence - genetics
Viruses
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Summary:The isolation and sequence comparison of avirulent and neurovirulent strains of polio virus, alpha virus, herpes virus, immunodeficiency virus, and other viruses have identified genetic changes that are required to cause disease in the nervous system. The molecular mechanisms by which these genetic changes result in neurovirulence are unknown. An avirulent laboratory strain of the Alphavirus Sindbis kills most cultured cell lines not by lethal parasitism, but by inducing apoptosis or programmed cell death. Transfection of cultured cells with the human bcl-2 oncogene can block Sindbis virus-induced apoptosis, resulting in a persistent viral infection resembling that observed in brains of immunodeficient mice. We investigated the possibility that neurovirulent strains of Sindbis virus could overcome the protective effects of bcl-2-a potential mechanism to explain the ability of these strains to cause fatal disease. Strains of Sindbis virus that were lethal for 2- to 4-week-old mice induced apoptotic death in cultured cells despite the presence of bcl-2. Using recombinant viruses, we show that a single amino acid change in the E2 glycoprotein of Sindbis virus confers both neurovirulence and the ability to kill cells expressing bcl-2.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.11.5202