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

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 was abolished. Several Env-mediated functions were analyzed to provide a mechanistic explanation for this selective adaptation. The change in host cell tropism was not caused by a switch to a SupT1-specific coreceptor. Biosynthesis of the variant Env glycoprotein was not improved in SupT1 cells, and in fact a small defect in intracellular Env processing was observed. SupT1 infection assays did not reveal an improved Env function either, and a dramatic loss of infectivity was measured with other cell types. The Env-mutated HIV-1 reached an approximately fivefold higher level of virus production in SupT1 cells at the peak of infection. Unlike the LAI virus, the variant did not trigger the formation of syncytia. Our combined results suggest that the HIV-1 variant allows the infected host cell to survive longer, thus producing more viral progeny. The intricate virus-cell interaction results in a balance between optimal virus replication and host cell survival, causing a cytopathic SI isolate to evolve toward a nonsyncytium-inducing (NSI) phenotype 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 the notion that HIV-1 evolution should always go from the NSI to SI phenotype.