title: Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex.
abstract: Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glyco-Gag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivo--namely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection.
authors.affiliation: Department of Microbiology, Abramson Cancer Center and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Stavrou
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nitta
authors.forename: Swathi
authors.initials: S
authors.lastname: Kotla
authors.forename: Dat
authors.initials: D
authors.lastname: Ha
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rein
authors.forename: Hung
authors.initials: H
authors.lastname: Fan
authors.forename: Susan R
authors.initials: SR
authors.lastname: Ross
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015683:Gene Products, gag / Q000378:metabolism* / Q000494:pharmacology; D006031:Glycosylation; D054884:Host-Pathogen Interactions / Q000502:physiology*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048348:Reverse Transcription / Q000502:physiology*
chemical_list: D017931:DNA Primers; D015683:Gene Products, gag; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase
keywords: intrinsic immunity; trex1; virus restriction factors