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nef alleles derived from a large number of individuals infected with human immunodeficiency virus type 1 (HIV-1) were analyzed to investigate the frequency of disrupted nef genes and to elucidate whether specific amino acid substitutions in Nef are associated with different stages of disease. We confirm that deletions or gross abnormalities in nef are rarely present. However, a comparison of Nef consensus sequences derived from 41 long-term nonprogressors 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 more frequently observed among nonprogressors, while nine features (an additional N-terminal PxxP motif, A15, R39, T51, T157, C163, N169, Q170, and M182) were more frequently found in progressors. Strong correlations between the frequency of these variations in Nef and both the CD4+-cell count and the viral load were observed. Moreover, analysis of sequential samples obtained from two progressors revealed that several variations in Nef, which were more commonly observed in patients with low CD4+-T-cell counts, were detected only during or after progression to immunodeficiency. Our results indicate that sequence variations in Nef are associated with different stages of HIV-1 infection and suggest a link between nef gene function and the immune status of the infected individual.

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HIV-1 subtype B predominates in the Republic of Korea. Phylogenetic analyses of sequences for complete nef genes and env gene fragments encoding the V3 loop have identified a major monophyletic Korean subclade that is distinct from Western subtype B sequences in the Los Alamos HIV Sequence Database. This was investigated further by sequence analysis of complete env genes recovered from the DNA of peripheral blood mononuclear cells for matched groups of Koreans, four patients per group, previously assigned as being infected with either Korean or Western strains. The phylogenetic classifications were confirmed and analysis of the translation products identified 32 amino acid signature pattern differences, dispersed throughout gp160, which differentiate the two subclades. Twenty-three of these positions map to epitopes recognized by HLA-I-restricted cytotoxic T-lymphocytes (CTL) as catalogued in the Los Alamos HIV Immunology Database. The remaining nine map at or close to sites predicted to be targets for immunoproteasomes that are involved in producing peptides that bind to MHC Class I. These results suggest that a founder effect in the Korean population is based on the spread of CTL-escape/host-adapted HIV-1 strains.