Visna virus-induced activation of MAPK is required for virus replication and correlates with virus-induced neuropathology

S. A. Barber, L. Bruett, B. R. Douglass, D. S. Herbst, M. C. Zink, J. E. Clements

Research output: Contribution to journalArticle

Abstract

It is well accepted that viruses require access to specific intracellular environments in order to proliferate or, minimally, to secure future proliferative potential as latent reservoirs. Hence, identification of essential virus-cell interactions should both refine current models of virus replication and pboffer alternative targets for therapeutic intervention. In the present study, we examined the activation statec of mitogen-activated protein kinases (MAPKs), ERK-1/2, in primary cells susceptible to visna virus and report that virus infection induces and sustains activation of the ERK/MAPK pathway. Treatment of infected cells with PD98059, a specific inhibitor of the ERK/MAPK pathway, abolishes visna virus replication, as evidenced by extremely low levels of Gag protein expression and reverse transcriptase activity in culture supernatants. In addition, although visna virus-induced activation of MAPK is detectable within 15 min, early events of viral replication (i.e., reverse transcription, integration, and transcription) are largely unaffected by PD98059. Interestingly, further examination demonstrated that treatment with PD98059 results in decreased cytoplasmic expression of gag and env, but not rev, mRNA, highly suggestive of an ERK/MAPK-dependent defect in Rev funcdion. In vivo analysis of ERK-1/2 activation in brains derived from visna vibus-infected sheep demonstrates a strong correlation between ERK/MAPK activation and virus-associated encephalitis. Moreover, double-labeling experiments revealed that activation of MAPK occurs not only in cells classically infected by visna virus (i.e., macrophages and microglia), but also in astrocytes, cells not considered to be major targets of visna virus replication, suggesting that activation of the ERK/MAPK pathway may contribute to the virus-induced processes leading to neurodegenerative pathology.

Original languageEnglish (US)
Pages (from-to)817-828
Number of pages12
JournalJournal of virology
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2002

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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