title: Changes in the extracellular envelope glycoprotein of variants that evolve during the course of simian immunodeficiency virus SIVMne infection affect neutralizing antibody recognition, syncytium formation, and macrophage tropism but not replication, cytopathicity, or CCR-5 coreceptor recognition.
abstract: Simian immunodeficiency virus SIVMne, like human immunodeficiency virus, evolves from a macrophage-tropic, non-syncytium-inducing virus at early times in infection to a T-cell-tropic, syncytium-inducing, cytopathic virus population over the course of progression to AIDS. Because the viruses isolated late in SIVMne infection of macaques include a complex mixture of variants, the viral determinants of such phenotypic changes have not been defined. To identify genetic changes that are important to virus evolution in the host, we constructed chimeric viruses by introducing variant envelope genes representative of proviruses throughout the course of infection and disease into the SIVMne parental clone (SIVMneCL8) that infected the macaque. The chimeric viruses expressed sequences encoding the surface unit of the envelope glycoprotein (Env-SU) of variants cloned between 35 and 170 weeks postinfection. The chimera with Env-SU from 35 weeks postinfection encoded only four changes in V1 compared to SIVMneCL8, whereas the chimeras encoding Env-SU from variants isolated later in infection encoded progressively more mutations both in V1 and elsewhere. Like SIVMneCL8, the chimeras were infectious for CEMx174 cells and macaque peripheral blood mononuclear cells. However, in contrast to SIVMneCL8, the chimeric viruses did not infect macaque macrophages, although each retained the ability to recognize the CCR-5 coreceptor. Thus, these data provide direct evidence that changes which evolve in Env-SU during the course of SIVMne infection do not alter CCR-5 interactions. Viruses encoding Env-SU from the latest times in infection (121 to 170 weeks postinfection), after disease was apparent, were syncytium inducing. However, these viruses were not highly cytopathic, suggesting that additional viral determinants may be required for the rapidly replicating, cytopathic phenotype of the uncloned mixed variant population. Changes in Env-SU did allow the virus to escape serum neutralizing antibodies that recognized the SIVMneCL8 parent. Moreover, the chimera encoding the Env-SU of a virus from 35 weeks postinfection, which differed from SIVMneCL8 only in V1, was not sensitive to neutralization by infected macaque sera, suggesting that V1 may define a portion of the principal neutralizing determinant for SIVMne. Together, these data suggest that SIV variants with changes in the Env-SU may be selected primarily by virtue of their ability to escape neutralizing antibody recognition.
authors.affiliation: Department of Microbiology, University of Washington, Seattle 98195, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Rudensey
authors.forename: J T
authors.initials: JT
authors.lastname: Kimata
authors.forename: E M
authors.initials: EM
authors.lastname: Long
authors.forename: B
authors.initials: B
authors.lastname: Chackerian
authors.forename: J
authors.initials: J
authors.lastname: Overbaugh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics; D003588:Cytopathogenic Effect, Viral; D005814:Genes, Viral; D014644:Genetic Variation; D006801:Humans; D008251:Macaca; D008264:Macrophages / Q000821:virology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D014162:Transfection; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins