Retroviruses, including HIV and HTLV, cause neurological disease. The goal of this project is to understand how retroviruses adversely affect the central nervous system. We are utilizing mouse retroviruses which cause rapid neurologic diseases (ie. 2-3 weeks after inoculation) and have used this system to study the interaction between virus and brain. Entry of virus into the brain: A non-structural glycosylated form of the viral gag polyprotein (glycogag) has long been recognized to be highly conserved among murine, feline and some primate retroviruses, but its function is as yet unknown. We have found that expression of this protein is a critical determinant neuroinvasiveness, and that this protein functions to enhance the spread of virus in vivo. Nonpathogenic mutant viruses which lack this protein rapidly generate revertants which have regained their pathogenicity for the brain. Sequence analysis of the revertants reveals a consistent mutation which generates a new start site for translation producing a slightly truncated protein. This indicates strong selective pressure favoring viruses which express glycogag. We are interested in understanding its function at the molecular level. In vitro model of neurodegeneration: We are continuing our efforts to develop a system whereby one can study at the molecular level the mechanism of retrovirus-induced neurodegeneration. We have initiated a study of embryonic cortical neurons cultured on a glial bed. This system has been used successfully by others to study neurotoxicity induced by excitatory neurotransmitters as well as hypoxia. These neurons are relevant since they are also susceptible to degeneration in virus- infected mice. Preliminary results suggest that supernatants from retrovirus-infected but not from uninfected pure microglial cultures cause neurotoxicity in this system. We plan to extend these studies to the analysis of microglia expressing individual viral genes and have constructed the appropriate expression vectors. Envelope gene: Two chimeric murine retroviruses which utilize the same receptor but differ in their envelope sequences have both been shown to infect the brain, and appear also to infect the same cell types in the brain. Both induce an intense diffuse astrocytosis, but only one causes clinical neurologic signs. We are very interested in this paradigm because of its analogy to brain infection by HIV, in which HIV envelope sequences of macrophage tropic viruses have been recovered from both demented and non-demented AIDS patients. We are currently looking for morphologic correlates of neurovirulence in these mice and are currently analyzing cytokine profiles in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000086-18
Application #
5200392
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1995
Total Cost
Indirect Cost
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

Showing the most recent 10 out of 14 publications