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

Cecilia Cheng-Mayer, Amanda Brown, Janet Harouse, Paul A Luciw, Allen J. Mayer

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5294-5300
Number of pages7
JournalJournal of Virology
Volume73
Issue number7
StatePublished - 1999

ASJC Scopus subject areas

  • Immunology

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