The ts1 mutant of Moloney murine leukemia virus-TB, unlike its leukemogenic parental virus, causes degenerative neurologic and immunologic disease after perinatal inoculation of susceptible strains of mice. The disease syndrome is characterized by development of noninflammatory spongiform myeloencephalopathyresulting in hindlimb paralysis and marked thymic atrophy associated withimmune deficiency. The differences in neurovirulence of ts1 and thenonneurovirulent wild type MoMuLV-TB have been attributed to two criticalmutations in the env gene of ts1 which result in two key pathologic features: a) enhanced ability to replicate in CNS, and b) neuropathogenicity. The former is most likely due to a Arg-430 Lys substitution and the latter is due to a Val-25 Ile substitution in the envelope precursor protein gPr80env. In certain strains of mice, both mutations in the viral env gene are necessary to induce hindlimb paralysis, whereas, in a highly susceptible strain of mice, FVB/N, only the Val-25 Ile substitution is necessary. It was also shown that at the restrictive temperature, the Val-25 Ile substitution in gPr80env of ts1 renders this protein inefficient in transport from the ER to the Golgi resulting in accumulation of this protein in the ER. The investigator hypothesizes that the cytopathic effect observed in neural cells of ts1-infected mice might be due to the accumulation of the gPr80env in the ER. Plans are presented here to further study indepth, at the molecular level, how the defective retroviral glycoproteins alter the normal physiologic functioning of natural target cells to produce cytopathic effects and degenerative disease. Studies to assess several possible mechanisms of cell killing caused by the ts1 and other mutants of ts1 will be performed. Dr. Wong also plans to introduce the env gene of the ts1 virus into the germline of mice to determine whether expression of defective glycoproteins alone in vivo, without complete viral replication or infectious virus production, can cause the degenerative disease syndrome characteristic of ts1. Complete pathological analyses of mice that successfully express the transgene will be performed. If successful, these experiments will not only prove that expression of a mutant retroviral glycoprotein can cause degenerative disease, but also will provide a useful tool for studying in detail the potential 54 effects of expresion of retroviral env gene alone on degenerative disease pathogenesis, as well as the host factors which contribute to the outcome of the disease. Furthermore, the studies proposed, using a well-defined retrovirus-mouse model, which the investigator feels mimics the etiology of AIDS and AIDS related diseases induced by human retroviruses, will help to better understand how retrovirus infections impair the host's immune and nervous systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA045124-07
Application #
3188096
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1986-08-01
Project End
1994-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Raofi, S; Wong, P K; Wilcox, R E (2000) Modulation of G-protein linked cAMP accumulation in immortalized murine cortical astrocytes by retroviral infection. Brain Res 862:230-3
Choe, W; Stoica, G; Lynn, W et al. (1998) Neurodegeneration induced by MoMuLV-ts1 and increased expression of Fas and TNF-alpha in the central nervous system. Brain Res 779:1-8
Lynn, W S; Wong, P K (1998) Neuroimmunopathogenesis of ts1 MoMuLV viral infection. Neuroimmunomodulation 5:248-60
Stoica, G; Barker, R; Wu, G et al. (1998) Quantitative variation of free amino acids in the central nervous system of MoMuLV-ts1-infected mice. In Vivo 12:395-401
Lin, Y C; Chow, C W; Yuen, P H et al. (1997) Establishment and characterization of conditionally immortalized astrocytes to study their interaction with ts1, a neuropathogenic mutant of Moloney murine leukemia virus. J Neurovirol 3:28-37
Yu, Y E; Choe, W; Zhang, W et al. (1997) Development of pathological lesions in the central nervous system of transgenic mice expressing the env gene of ts1 Moloney murine leukemia virus in the absence of the viral gag and pol genes and viral replication. J Neurovirol 3:274-82
Wong, P K; Saha, K; Lin, Y C et al. (1996) Long-term cultivation and productive infection of primary thymocyte cultures by a thymocytopathic murine retrovirus. Virology 215:203-6
Lynn, W S; Wong, P K (1995) Neuroimmunodegeneration: do neurons and T cells use common pathways for cell death? FASEB J 9:1147-56
Saha, K; Hollowell, D; Wong, P K (1994) Mother-to-baby transfer of humoral immunity against retrovirus-induced neurologic disorders and immunodeficiency. Virology 198:129-37
Shikova, E; Lin, Y C; Saha, K et al. (1993) Correlation of specific virus-astrocyte interactions and cytopathic effects induced by ts1, a neurovirulent mutant of Moloney murine leukemia virus. J Virol 67:1137-47

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