TY - JOUR
T1 - Selection for neutralization resistance of the simian/human immunodeficiency virus SHIV(SF33A) variant in vivo by virtue of sequence changes in the extracellular envelope glycoprotein that modify N-linked glycosylation
AU - Cheng-Mayer, Cecilia
AU - Brown, Amanda
AU - Harouse, Janet
AU - Luciw, Paul A.
AU - Mayer, Allen J.
PY - 1999
Y1 - 1999
N2 - We previously reported on the in vivo adaptation of an infectious molecular simian/human immunodeficiency virus (SHIV) clone, SHIV(SF33), into a pathogenic biologic viral variant, designated SHIV(SF33A). In the present study, we show that SHIV(SF)33(A) is resistant to neutralization by human immunodeficiency virus (HIV) and SHIV antisera. Multiple amino acid substitutions accumulated over time throughout the env gene of SHIV(SF)33(A); some of them coincided with the acquisition of the neutralization resistance of the virus. Of interest are changes that resulted in the removal, repositioning, and addition of potential glycosylation sites within the V1, V2, and V3 regions of envelope gp120. To determine whether potential glycosylation changes within these principal neutralization domains of HIV type 1 formed the basis for the resistance to serum neutralization of SHIV(SF33A), mutant viruses were generated on the backbone of parental SHIV(SF33) and tested for their neutralization sensitivity. The mutations generated did not alter the in vitro replication kinetics or cytopathicity of the mutant viruses in T-cell lines. However, the removal of a potential glycosylation site in the V1 domain or the creation of such a site in the V3 domain did allow the virus to escape serum neutralization antibodies that recognized parental SHIV(SF33). The combination of the V1 and V3 mutations conferred an additive effect on neutralization resistance over that of the single mutations. Taken together, these data suggest that (i) SHIV variants with changes in the Env SU can be selected in vivo primarily by virtue of their ability to escape neutralizing antibody recognition and (ii) carbohydrates play an important role in conferring neutralization escape, possibly by altering the structure of envelope gp120 or by shielding principal neutralization sites.
AB - We previously reported on the in vivo adaptation of an infectious molecular simian/human immunodeficiency virus (SHIV) clone, SHIV(SF33), into a pathogenic biologic viral variant, designated SHIV(SF33A). In the present study, we show that SHIV(SF)33(A) is resistant to neutralization by human immunodeficiency virus (HIV) and SHIV antisera. Multiple amino acid substitutions accumulated over time throughout the env gene of SHIV(SF)33(A); some of them coincided with the acquisition of the neutralization resistance of the virus. Of interest are changes that resulted in the removal, repositioning, and addition of potential glycosylation sites within the V1, V2, and V3 regions of envelope gp120. To determine whether potential glycosylation changes within these principal neutralization domains of HIV type 1 formed the basis for the resistance to serum neutralization of SHIV(SF33A), mutant viruses were generated on the backbone of parental SHIV(SF33) and tested for their neutralization sensitivity. The mutations generated did not alter the in vitro replication kinetics or cytopathicity of the mutant viruses in T-cell lines. However, the removal of a potential glycosylation site in the V1 domain or the creation of such a site in the V3 domain did allow the virus to escape serum neutralization antibodies that recognized parental SHIV(SF33). The combination of the V1 and V3 mutations conferred an additive effect on neutralization resistance over that of the single mutations. Taken together, these data suggest that (i) SHIV variants with changes in the Env SU can be selected in vivo primarily by virtue of their ability to escape neutralizing antibody recognition and (ii) carbohydrates play an important role in conferring neutralization escape, possibly by altering the structure of envelope gp120 or by shielding principal neutralization sites.
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U2 - 10.1128/jvi.73.7.5294-5300.1999
DO - 10.1128/jvi.73.7.5294-5300.1999
M3 - Article
C2 - 10364275
AN - SCOPUS:0033033625
SN - 0022-538X
VL - 73
SP - 5294
EP - 5300
JO - Journal of virology
JF - Journal of virology
IS - 7
ER -