Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS

The human immunodeficiency virus type 1 (HIV-1) Nef protein has several ind ependent functions that might contribute to efficient viral replication in vivo. Since HIV-1 adapts rapidly to its host environment, we investigated i f different Nef properties are associated with disease progression. Functio nal analysis revealed that nef alleles obtained during late stages of infec tion did not efficiently downmodulate class I major histocompatibility comp lex but were highly active in the stimulation of viral replication. In comp arison, functional activity in downregulation of CD4 and enhancement of HIV -1 infectivity were maintained or enhanced after AIDS progression. Our resu lts demonstrate that various Nef activities are modulated during the course of HIV-1 infection to maintain high viral loads at different stages of dis ease progression. These findings suggest that all in vitro Nef functions in vestigated contribute to AIDS pathogenesis and indicate that nef variants w ith increased pathogenicity emerge in a significant number of HIV-l-infecte d individuals.