HIV-1 evolves into a nonsyncytium-inducing virus upon prolonged culture invitro

HIV-1 LAI is a syncytium-inducing (SI) virus with a broad host cell range. We previously isolated a LAI variant that improved replication in the SupT1 T cell line due to mutations within the C1 and C4 constant regions of the Env protein. We now report that this variant exhibits a severely restricted host cell range, as replication in other T cell lines and primary cells wa s abolished. Several Env-mediated functions were analyzed to provide a mech anistic explanation for this selective adaptation. The change in host cell tropism was not caused by a switch to a SupT1-specific coreceptor. Biosynth esis of the variant Env glycoprotein was not improved in SupT1 cells, and i n fact a small defect in intracellular Env processing was observed. SupT1 i nfection assays did not reveal an improved Env function either, and a drama tic loss of infectivity was measured with other cell types. The Env-mutated HIV-1 reached an approximately fivefold higher level of virus production i n SupT1 cells at the peak of infection. Unlike the LAI virus, the variant d id not trigger the formation of syncytia. Our combined results suggest that the HIV-I variant allows the infected host cell to survive longer, thus pr oducing more viral progeny. The intricate virus-cell interaction results in a balance between optimal virus replication and host cell survival, causin g a cytopathic SI isolate to evolve toward a nonsyncytium-inducing (NSI) ph enotype in cell culture. These findings may help explain the absence of SI variants in the initial phase of HIV-1 infection, and the results dispute t he notion that HIV-I evolution should always go from the NSI to SI phenotyp e. (C) 1999 Academic Press.