Substitution of leucine for isoleucine in a sequence highly conserved among retroviral envelope surface glycoproteins attenuates the lytic effect of the Friend murine leukemia virus.
Friend murine leukemia virus is a replication-competent retrovirus that contains no oncogene and that exerts lytic and leukemogenic properties. Thus, newborn mice inoculated with Friend murine leukemia virus develop severe early hemolytic anemia before appearance of erythroleukemia. To identify the retroviral determinants regulating these effects, we used chimeric infectious constructions and site-directed point mutations between a virulent Friend murine leukemia virus strain and a naturally occurring variant attenuated in lytic and leukemogenic effects. We found that severe hemolytic anemia was always associated with higher numbers of blood reticulocytes with budding retroviral particles. Furthermore, a remarkably conservative leucine to isoleucine change in the extracellular SU component of the retroviral envelope was sufficient to attenuate this lytic effect. Also, this leucine at position 348 of the envelope precursor protein was located within the only stretch of five amino acids that is conserved in the extracellular SU component of all murine, feline, and primate type C and type D retroviral envelopes. This observation suggested an important structural function for this yet undescribed conserved sequence of the envelope. Lastly, we observed that lytic and leukemogenic effects were attenuated by a deletion of a second repeat in the transcriptional enhancer region of the viral long terminal repeats of the variant strain.
Sitbon
M
M
Laboratoire d'Immunologie et Oncologie des Maladies Rétrovirales, Institut National de la Santé et de la Recherche Médicale Unité, Paris, France.
d'Auriol
L
L
Ellerbrok
H
H
André
C
C
Nishio
J
J
Perryman
S
S
Pozo
F
F
Hayes
S F
SF
Wehrly
K
K
Tambourin
P
P
D000595:Amino Acid Sequence; D000743:Anemia, Hemolytic / Q000382:microbiology*; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005622:Friend murine leukemia virus / Q000472:pathogenicity*; D015686:Gene Products, env / Q000502:physiology*; D006461:Hemolysis; D007532:Isoleucine; D007930:Leucine; D004915:Leukemia, Erythroblastic, Acute / Q000382:microbiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000502:physiology*
D015686:Gene Products, env; D009841:Oligonucleotides; D014759:Viral Envelope Proteins; D007532:Isoleucine; D007930:Leucine