Properties of the Surface Envelope Glycoprotein Associated with Virulence of Simian-Human Immunodeficiency Virus SHIV _SF33A Molecular Clones

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.

Induction of Simian AIDS in Infant Rhesus Macaques Infected with CCR5- or CXCR4-Utilizing Simian-Human Immunodeficiency Viruses Is Associated with Distinct Lesions of the Thymus

“…Studies on the dualtropic SHIV 89.6 and its pathogenic derivatives indicate that the fusogenic potential of the env gene is directly related to virus load and pathogenicity of virus in adult macaques (11,12). Interestingly, both SHIV SF162P3 and SHIV SF33A established similar levels of plasma viremia and rapid progression to AIDS, although the former virus contained an env gene that was less fusogenic than the latter (8,17). Taken together, these findings suggest that the biological behavior of dualtropic viruses may be different from that of either CCR5 or CXCR4 monotropic strains.…”

Vesicular Stomatitis Virus Glycoprotein Is a Determinant of Pathogenesis in Swine, a Natural Host

“…Changes in the surface envelope gly- VOL. 77, 2003 VSV GLYCOPROTEIN IS ASSOCIATED WITH VIRULENCE IN SWINE 8045 coprotein of simian-human immunodeficiency virus molecular clones have also been reported to be responsible for increases in fusion capacity, cytopathicity, replication capacity, and neutralization resistance (8).…”

Influence of Long Terminal Repeat and Env on the Virulence Phenotype of Equine Infectious Anemia Virus

“…The role of env sequences in lentivirus virulence has been clearly demonstrated in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques (7,8,11,12,16,20,22,27,43). As few as 12 amino acid differences in the env sequence are sufficient to change pathogenic potential of SHIV clones (43).…”

“…As few as 12 amino acid differences in the env sequence are sufficient to change pathogenic potential of SHIV clones (43). Most of the env changes that arise with increased virulence are localized to gp120 variable regions; changes in the number and position of N-linked glycosylation sites are common (7,8,16,27,43). Some measurable differences in virulent SHIVs that have been attributed to env sequence changes include fusogenicity, resistance to neutralization, and increased replicative potential (7,8,43).…”