1887

Abstract

Our previous studies have shown that human immunodeficiency virus type 1 (HIV-1), with mutations in accessory genes such as or can generate persistent infection of MT-4 cells, whereas infection by wild-type or mutant HIV-1 causes extensive cell death. The possibility of generating a naturally attenuated form of HIV-1 with reduced cytopathogenicity in MT-4 cells was examined by serial passage of the wild-type and a mutant form of HIV-1, each derived from the infectious molecular clone pNL432. The ability to cause persistent infection was observed after four passages of wild-type HIV-1 with the frequency of persistence becoming progressively higher with serial passage. In contrast, persistent infection was not observed even after 50 passages of the mutant virus. Sequence analysis of the accessory gene loci in genomes recovered from the persistent infections caused by passaged virus revealed mutations in and but not in The processing of the Env precursor to mature forms was not modified in any of the passages of either wild-type or mutant HIV-1. However, when compared with acute infections caused by similarly passaged virus of both wild-type and ne/mutant HIV-1, persistent infections by passaged wild-type HIV-1 showed a significant decrease in the cell surface expression and function of Env. Cell surface CD4 was only partially down-regulated on cells acutely infected with the passaged viruses, whereas on cells persistently infected with passaged wild-type HIV-1 it was completely down- regulated. These results suggest that, during serial passage of HIV-1, mutations accumulate at least in the accessory genes and in parallel with a lesser interaction between cell surface Env and CD4 molecules, and lead to the generation of less cytopathogenic viruses capable of persistent infection. Our results also suggest an important role for the gene product in the generation of HIV-1 strains that are less cytopathogenic.

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1994-09-01
2022-01-26
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