Alteration from T- to B-Cell Tropism Reduces Thymic Atrophy and Cytocidal Effects in Thymocytes but not Neurovirulence Induced by ts1, a Mutant of Moloney Murine Leukemia Virus TB

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 20; pp. 8991 - 8995
• Main Authors: Paul K. Y. Wong, Szurek, Paul F., Floyd, Eugenie, Saha, Kunal, Brooks, Benjamin R.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.10.1991; National Acad Sciences
• Subjects: 3T3 cells; Animals; Atrophy; B-Lymphocytes - microbiology; B-Lymphocytes - pathology; Base Sequence; Biological and medical sciences; Cell Death; Cell Line; Cell lines; Chimera; Cloning, Molecular; Corticosterone - blood; DNA, Viral - genetics; Fundamental and applied biological sciences. Psychology; Genome, Viral; Infections; Mice; Microbiology; Molecular Sequence Data; Moloney murine leukemia virus - genetics; Moloney murine leukemia virus - immunology; Moloney murine leukemia virus - pathogenicity; Mutation; Neurons; Paralysis; Paralysis - blood; Paralysis - microbiology; Paralysis - pathology; Plasmids; Repetitive Sequences, Nucleic Acid; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Spinal cord; Spleen; T lymphocytes; T-Lymphocytes - microbiology; T-Lymphocytes - pathology; Thymocytes; Thymus Gland - pathology; Virology; Virulence - genetics; Viruses; Infectious focus; Tropism; Immunopathology; Oncovirinae; Nervous system diseases; Thymus gland; Recombinant virus; Rodentia; Retroviridae; Nervous system; Virus; Encephalomyelopathy; Vertebrata; Mammalia; Lymphoid organ; Mouse; Type C oncovirus; Atrophia; Replication; Murine leukemia virus; Degenerative disease; LTR sequence; Temperature sensitive mutation; Slow virus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.20.8991

The ts1 mutant of Moloney murine leukemia virus TB causes degenerative neurologic and immunologic disease in mice, characterized by development of spongiform encephalomyelopathy resulting in hindlimb paralysis, marked thymic atrophy associated with immunodeficiency, and generalized body wasting. To investigate the pathogenesis of the thymic atrophy caused by ts1, we constructed a chimeric virus, ts1-Cas(NS), in which a major portion of the U3 region of the long terminal repeat of ts1, a T-lymphotropic and neurovirulent murine leukemia virus, was replaced by the corresponding U3 region of Cas-Br-E, a B-lymphotropic and neurovirulent murine leukemia virus. In FVB/N mice, ts1-Cas(NS) induced paralytic and wasting disease with incidence, severity, and latency similar to that induced by ts1, but it failed to cause thymic atrophy as severe as that observed in ts1-infected mice. Furthermore, thymocytes cultured from ts1-Cas(NS)-infected mice died at a much slower rate than those of ts1-infected mice. The U3 substitution in ts1-Cas(NS) specifically diminished the ability of the virus to replicate in the thymus, whereas viral replication in the spinal cord was not significantly affected; thus, neurovirulence was not changed. The correlation of reduced thymic atrophy with decreased thymic viral titers and the decreased ability of ts1-Cas(NS) to cause thymocyte death in mice suggest strongly that the marked thymic atrophy in ts1-infected mice is not an indirect effect occurring secondary to neurodegenerative and wasting disease but is a direct cytopathic effect of high-level viral replication in the thymus.