A Val-25-to-Ile substitution in the envelope precursor polyprotein, gPr80env, is responsible for the temperature sensitivity, inefficient processing of gPr80env, and neurovirulence of ts1, a mutant of Moloney murine leukemia virus TB

Abstract

tsl is a neurovirulent spontaneous temperature-sensitive mutant of Moloney murine leukemia virus TB which causes hindlimb paralysis in mice. Previously, 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 two cleavage products, gp7O and Prpl5E. This inefficient processing of gPr8Oe"v is correlated with neurovirulence. In this study, it was shown that a single amino acid substitution, Val-25-Ile in gPr80"v, is responsible for the temperature sensitivity, inefficient processing of gPr8(W'v at the restrictive temperature, and neurovirulence of tsl. At the restrictive temperature, a steady-state level of nonprocessed, endoglycosidase H-sensitive gPr8Oenv remained in the endoplasmic reticulum of cells infected by tsl, but no endoglycosidase H-resistant gPr8Oe"v and only trace amounts of gp70 were detected in the infected cells. Since the host cell-encoded processing protease resides in the cis cisternae of the Golgi apparatus, inefficient processing of gPr80e"V at the restrictive temperature is. most likely due to inefficient transport of gPr8 env from the endoplasmic reticulum to the cis cisternae of the Golgi apparatus rather than due to misfolded gPr80rnV being a poor substrate for the processing protease at the restrictive temperature.

A Viral Non‐Coding Region Determining Neuropathogenicity of Murine Leukemia Virus A8 Is Responsible for Envelope Protein Expression in the Rat Brain

“…The protein gp70 was observed primarily in the brains of rats infected with R7f and Rec5. It has been reported that the accumulation of uncleaved envelope precursor protein (gpr85), or the presence of Env protein with differential processing of N-linked sugar, as found in the cells infected by neuropathogenic MLVs, is an important factor in manifestation of spongiosis (3,7,8,13,14). In this study, we did not observe an abundance of gpr85 or Env with differential processing of N-linked sugar in the brains of R7finfected rats ( Fig.…”

“…Some uninfected neurons exhibit cytopathogenicity in the brains of rats infected with neuropathogenic viruses, indicating an indirect mechanism for MLV-induced neuropathogenicity (11,18). It has been suggested that the uncleaved Env precursor protein, or Env protein with differential processing of N-linked sugar, is correlated with retrovirus-induced spongiform neurodegeneration (3,7,8,13,14). However, the pathomechanism of spongiosis induced by Env is still not understood.…”

Two separate envelope regions influence induction of brain disease by a polytropic murine retrovirus (FMCF98)

“…Two separate neurovirulence determinants have also been described in the envelope gene of Moloney MuLV TB mutant ts1: one in the amino-terminal half of gp70 which affected the stability and processing of the precursor protein and the other in carboxy-terminal p15E which enhanced replication in the central nervous system (25,(28)(29)(30). However, in ts1, the determinants could not act independently of each other to induce the same clinical signs (24,26,28,30).…”

Characterization of a neurologic disease induced by a polytropic murine retrovirus: evidence for differential targeting of ecotropic and polytropic viruses in the brain

“…Included among this group are two temperature-sensitive mutants of Moloney murine leukemia virus (MuLV) (3,37), a variant of Friend MuLV (17,19), and CasBr, a virus recovered from wild mice (12). Mapping studies have indicated that the primary determinants of neurovirulence reside within the respective envelope genes (10,24,35). However, the role of the viral envelope gene in disease pathogenesis is not understood.…”