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

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Abstract
In vivo adaptation of simian-human immunodeficiency virus (SHIV) clone SHIV SF33 resulted in the emergence of pathogenic isolate SHIV SF33A , which caused a rapid and severe CD4 + T-cell depletion when inoculated into rhesus macaques. Two molecular clones generated by inserting the env V1-to-V5 region amplified from SHIV SF33A -infected animals into the parental SHIV SF33 genome retained a pathogenic phenotype. The gp120 envelope glycoproteins of pathogenic clones SHIV SF33A2 and SHIV 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 + T-cell cultures. Last, gp120 carried the determinants of SHIV SF33A neutralization resistance. Thus, changes in SHIV SF33A gp120 produced a set of properties that could account for the pathogenic phenotype observed in vivo. Measurement of antibody binding to SHIV 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 SF33A clones folded in a conformation that was primed for interaction with CXCR4 or for the subsequent step of fusion.

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