It has recently been recognized that some human retroviruses are capable of replicating in the central nervous system. Their participation in CNS pathology is as yet a matter of speculation. We are studying a murine retrovirus (WM-E) which was originally isolated from wild mice and has the capacity to cause a lower-motor-neuron paralytic disease in some strains of laboratory mice with a 12-20 week latency. The primary goal of this project is to identify the cells in the CNS which replicate this virus and the mechanisms by which this virus cause motor neuron pathology. We have prepared a panel of monoclonal antibodies specific for WM-E in AKR mice which are tolerant to endogenous retrovirus. These antibodies react with the three viral membrane-associated proteins gp70, p15(E) and P15gag and express no cross-reactivity with endogenous viruses of laboratory mice. Using these antibodies to follow virus replication, we have found that neonatal inoculation of both susceptible (NFS) and resistant (AKR, NZB) strains of mice resulted in quantitatively equivalent levels of WM-E virus replication in the spleen and comparable levels of viremia. We have documented that the virus does indeed replicate in the lumbar spinal cord by both immunohistochemistry and infectious center assay of trypsin/collagenase-disrupted tissue. However, no significant difference was found in the levels of virus replication in the lumbar cord of susceptible and resistant strains of mice. In addition, retroviruses which do not cause neurologic disease also replicated in the CNS, but the patterns of replication as detected by EM appear different when compared with that of WM-E. We are currently studying primary cultures of lumbar cord cells in order to identify the specific cell types which are infected by these various viruses. Another retrovirus has now been identified which is unrelated to WM-E, but which also causes paralytic disease in mice. This virus is being molecularly cloned by B. Chesebro and should prove useful in identifying viral genomic sequences responsible for the neuropathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000086-08
Application #
4688348
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Portis, J L; Askovich, P; Austin, J et al. (2009) The degree of folding instability of the envelope protein of a neurovirulent murine retrovirus correlates with the severity of the neurological disease. J Virol 83:6079-86
Clase, Amanda C; Dimcheff, Derek E; Favara, Cynthia et al. (2006) Oligodendrocytes are a major target of the toxicity of spongiogenic murine retroviruses. Am J Pathol 169:1026-38
Trifilo, Matthew J; Yajima, Toshitaka; Gu, Yusu et al. (2006) Prion-induced amyloid heart disease with high blood infectivity in transgenic mice. Science 313:94-7
Dimcheff, Derek E; Faasse, Mark A; McAtee, Frank J et al. (2004) Endoplasmic reticulum (ER) stress induced by a neurovirulent mouse retrovirus is associated with prolonged BiP binding and retention of a viral protein in the ER. J Biol Chem 279:33782-90
Dimcheff, Derek E; Portis, John L; Caughey, Byron (2003) Prion proteins meet protein quality control. Trends Cell Biol 13:337-40
Dimcheff, Derek E; Askovic, Srdjan; Baker, Audrey H et al. (2003) Endoplasmic reticulum stress is a determinant of retrovirus-induced spongiform neurodegeneration. J Virol 77:12617-29
Portis, John L (2002) Perspectives on the role of endogenous human retroviruses in autoimmune diseases. Virology 296:1-5
Igietseme, J U; Portis, J L; Perry, L L (2001) Inflammation and clearance of Chlamydia trachomatis in enteric and nonenteric mucosae. Infect Immun 69:1832-40
Askovic, S; Favara, C; McAtee, F J et al. (2001) Increased expression of MIP-1 alpha and MIP-1 beta mRNAs in the brain correlates spatially and temporally with the spongiform neurodegeneration induced by a murine oncornavirus. J Virol 75:2665-74
Peterson, K E; Robertson, S J; Portis, J L et al. (2001) Differences in cytokine and chemokine responses during neurological disease induced by polytropic murine retroviruses Map to separate regions of the viral envelope gene. J Virol 75:2848-56

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