Sequence variations in human immunodeficiency virus type 1 Nef are associated with different stages of disease

nef alleles derived from a large number of individuals infected with human immunodeficiency virus type 1 (HIV-1) were analyzed to investigate the freq uency of disrupted nef genes and to elucidate whether specific amino acid s ubstitutions in Nef are associated with different stages of disease. We con firm that deletions or gross abnormalities in nef are rarely present. Howev er, a comparison of Nef consensus sequences derived from 41 long-term nonpr ogressors and from 50 individuals with progressive HIV-1 infection revealed that specific variations are associated with different stages of infection . Five amino acid variations in Nef (T15, N51, H102, L170, and E182) were m ore frequently observed among nonprogressors, while nine features (an addit ional N-terminal PxxP motif, A15, R39, T51, T157, C163, N169, Q170, and M18 2) were more frequently found in progressors. Strong correlations between t he frequency of these variations in Nef and both the CD4(+)-cell count and the viral load were observed. Moreover, analysis of sequential samples obta ined from two progressors revealed that several variations in Nef, which we re more commonly observed in patients with low CD4(+)-T-cell counts, were d etected only during or after progression to immunodeficiency, Our results i ndicate that sequence variations in Nef are associated with different stage s of HIV-1 infection and suggest a link between nef gene function and the i mmune status of the infected individual.