Properties of the Surface Envelope Glycoprotein Associated with Virulence of Simian-Human Immunodeficiency Virus SHIV sub(SF33A) Molecular Clones

• Published in: Journal of virology 2002-02, Vol.76 (4), p.1588-1599
• Main Authors: Chakrabarti, LA, Ivanovic, T, Cheng-Mayer, C
• Format: Article
• Language: English
• Subjects: CD4 antigen; glycoprotein gp120; Simian/human immunodeficiency virus
• ISSN: 0022-538X
• DOI: 10.1128/JVI.76.4.1588-1599.2002

In vivo adaptation of simian-human immunodeficiency virus (SHIV) clone SHIV sub(SF33) resulted in the emergence of pathogenic isolate SHIV sub(SF33A), which caused a rapid and severe CD4 super(+) T-cell depletion when inoculated into rhesus macaques. Two molecular clones generated by inserting the env V1-to- V5 region amplified from SHIV sub(SF33A)-infected animals into the parental SHIV sub(SF33) genome retained a pathogenic phenotype. The gp120 envelope glycoproteins of pathogenic clones SHIV sub(SF33A2) and SHIV sub(SF33A5) conferred a threefold increase in viral entry and fusogenicity compared to the parental glycoprotein. Changes in gp120 were also responsible for a higher replication capacity and cytopathicity in primary CD4 super(+) T-cell cultures. Last, gp120 carried the determinants of SHIV sub(SF33A) neutralization resistance. Thus, changes in SHIV sub(SF33A) gp120 produced a set of properties that could account for the pathogenic phenotype observed in vivo. Measurement of antibody binding to SHIV sub(SF33A) viral particles revealed an increased exposure of the CD4- induced epitope recognized by the 17b monoclonal antibody in a region that was shown to contribute to coreceptor binding. Exposure of this epitope occurred in the absence of CD4 binding, suggesting that the envelope glycoprotein of pathogenic SHIV sub(SF33A) clones folded in a conformation that was primed for interaction with CXCR4 or for the subsequent step of fusion.