Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
MOLECULAR ANALYSIS OF A NEUROVIRULENT MURINE LEUKEMIA VIRUS, TS1
Diss Abstr Int [B]; 52(3):1228 1991. Unique Identifier : AIDSLINE ICDB/92679043 Szurek PF; Univ. of Texas H.S.C. at Houston Grad. Sch. of Biomed. Sci.
Abstract:
ts1 is a neurovirulent spontaneous temperature-sensitive mutant of Moloney murine leukemia virus TB (MoMuLV-TB). MoMuLV-TB causes T-cell lymphoma or lymphoid leukemia in mice after a long latency period whereas ts1 causes a progressive hindlimb paralytic disease after a much shorter latency period. In previous studies, it had been shown that the temperature-sensitive defect resided in the env gene. At the restrictive temperature, the envelope precursor polyprotein, gPr80env, is inefficiently processed intracellularly into a heterodimer consisting of two cleavage products, gp70 and Prp15E. This inefficient processing is correlated with neurovirulence. In this study, the nucleotide sequences of the env genes for both ts1 and MoMuLV-TB were determined, and the encoded amino acid sequences were deduced from the DNA sequences. There were four unique amino acid substitutions in the gPr80env of ts1. In order to determine which unique amino acid was responsible for the phenotypic characteristics of ts1, a set of hybrid genomes was constructed by exchanging restriction fragments between ts1 and MoMuLV-TB. NIH 3T3 cells were transfected with the hybrid genomes to obtain infectious hybrid viruses. Assays of the hybrid viruses showed that a Val-25----Ile substitution in gPr80env was responsible for the temperature sensitivity, inefficient processing, and neurovirulence of ts1. In further studies, the Ile-25 in gPr80env was substituted with Thr, Ala, Leu, Gly, and Glu by site-directed mutagenesis to generate a new set of mutant viruses, ie, ts1-T, A, -L, -G, and -E, respectively. The rank order of the mutants for temperature sensitivity was: ts1-E greater than ts1-G greater than ts1-L greater than ts1-A greater than ts1 greater than ts1-T. The degree of temperature sensitivity of each of the mutants also correlated with the degree of inefficient processing of gPr80env. The mutant viruses were assayed for neurovirulence. ts1-T caused whole body tremor, ts1-A caused hindlimb paralysis, ts1-L caused paraparesis, but ts1-G and -E were not neurovirulent. These results show that inefficient processing of gPr80env is correlated with neurovirulence, but if processing of gPr80env is too inefficient there is no neurovirulence. Furthermore, the disease profile of each of the neurovirulent viruses depends on the degree of inefficient processing of gPr80env. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-21831).
Keywords: Amino Acid Sequence Animal Gene Products, env/*GENETICS Genes, Viral/GENETICS Hindlimb Hybridization Leukemia Viruses, Murine/*GENETICS Paralysis/ETIOLOGY/MICROBIOLOGY Temperature Virulence THESIS 920430
M9240942
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
