Increase in soluble CD4 binding to and CD4-induced dissociation of gp120 from virions correlates with infectivity of human immunodeficiency virus type 1.
Mutations in the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins gp120 and gp41, previously shown to confer an enhanced replicative capacity and broadened host range to the ELI1 strain of HIV-1, were analyzed for their biochemical effects on envelope structure and function. The tendency of purified virions to release their extracellular gp120 component, either spontaneously or after interacting with soluble CD4 (CD4-induced shedding) was assessed. A single amino acid substitution in part of the CD4 binding site of gp120 (Gly-427 to Arg) enhanced both spontaneous and CD4-induced shedding of gp120 from virions, while a single change in the fusogenic region of gp41 (Met-7 to Val) affected only CD4-induced shedding. Although each codon change alone conferred increased growth ability, virus with both mutations exhibited the most rapid replication kinetics. In addition, when both of these mutations were present, virions had the highest tendency to shed gp120, both spontaneously and after exposure to soluble CD4. Analysis of CD4 binding to virion-associated gp120 showed that the changes in both gp120 and gp41 contributed to increased binding. These results demonstrated that the increased replicative capacity of the ELI variants in human CD4+ cell lines was associated with altered physical and functional properties of the virion envelope glycoproteins.
Willey
R L
RL
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Martin
M A
MA
Peden
K W
KW
D000220:Adaptation, Biological / Q000235:genetics; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014771:Virion / Q000187:drug effects / Q000378:metabolism*; D014779:Virus Replication
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G