Evolution of the HIV-1 envelope glycoproteins with a disulfide bond between gp120 and gp41.
BACKGROUND
We previously described the construction of an HIV-1 envelope glycoprotein complex (Env) that is stabilized by an engineered intermolecular disulfide bond (SOS) between gp120 and gp41. The modified Env protein antigenically mimics the functional wild-type Env complex. Here, we explore the effects of the covalent gp120 - gp41 interaction on virus replication and evolution.


RESULTS
An HIV-1 molecular clone containing the SOS Env gene was only minimally replication competent, suggesting that the engineered disulfide bond substantially impaired Env function. However, virus evolution occurred in cell culture infections, and it eventually always led to elimination of the intermolecular disulfide bond. In the course of these evolution studies, we identified additional and unusual second-site reversions within gp41.


CONCLUSIONS
These evolution paths highlight residues that play an important role in the interaction between gp120 and gp41. Furthermore, our results suggest that a covalent gp120 - gp41 interaction is incompatible with HIV-1 Env function, probably because this impedes conformational changes that are necessary for fusion to occur, which may involve the complete dissociation of gp120 from gp41.
Sanders
Rogier W
RW
Dept. of Human Retrovirology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. r.w.sanders@amc.uva.nl
Dankers
Martijn M
MM
Busser
Els
E
Caffrey
Michael
M
Moore
John P
JP
Berkhout
Ben
B
D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D004220:Disulfides / Q000032:analysis; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D014162:Transfection; D014779:Virus Replication
D004220:Disulfides; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41