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, ANDMACROPHAGE TROPISM BUT NOT REPLICATION, CYTOPATHICITY, OR CCR-5 CORECEPTOR RECOGNITION

Simian immunodeficiency virus SIVMne, like human immunodeficiency viru s, evolves from a macrophage-tropic, non-syncytium-inducing virus at e arly times in infection to a T-cell-tropic, syncytium-inducing, cytopa thic virus population over the course of progression to AIDS, Because the viruses isolated late in SIVMne infection of macaques include a co mplex mixture of variants, the viral determinants of such phenotypic c hanges have not been defined, To identify genetic changes that are imp ortant to virus evolution in the host, we constructed chimeric viruses by introducing variant envelope genes representative of proviruses th roughout the course of infection and disease into the SIVMne parental clone (SIVMneCL8) that infected the macaque. The chimeric viruses expr essed sequences encoding the surface unit of the envelope glycoprotein (Env-SU) of variants cloned between 35 and 170 weeks postinfection. T he chimera with Env-SU from 35 weeks postinfection encoded only four c hanges in V1 compared to SIVMneCL8, whereas the chimeras encoding Env- SU from variants isolated later in infection encoded progressively mor e mutations both in V1 and elsewhere. Like SIVMneCL8, the chimeras wer e infectious for CEMx174 cells and macaque peripheral blood mononuclea r cells, However, in contrast to SIVMneCL8, the chimeric viruses did n ot infect macaque macrophages, although each retained the ability to r ecognize the CCR-5 coreceptor. Thus, these data provide direct evidenc e that changes which evolve in Env-SU during the course of SIVMne infe ction do not alter CCR-5 interactions. Viruses encoding Env-SU from th e latest times in infection (121 to 170 weeks postinfection), after di sease was apparent, were syncytium inducing, However, these viruses we re not highly cytopathic, suggesting that additional viral determinant s may be required for the rapidly replicating, cytopathic phenotype of the uncloned mixed variant population, Changes in Env-SU did allow th e virus to escape serum neutralizing antibodies that recognized the SI VMneCL8 parent, Moreover, the chimera encoding the Env-SU of a virus f rom 35 weeks postinfection, which differed from SIVMneCL8 only in V1, was not sensitive to neutralization by infected macaque sera, suggesti ng that V1 may define a portion of the principal neutralizing determin ant for SIVMne, Together, these data suggest that SIV variants with ch anges in the Env-SU may be selected primarily by virtue of their abili ty to escape neutralizing antibody recognition.