Abstract
BackgroundHIV-1 subtype C Nef sequences have a significantly lower ability overall to down-regulate CD4 and HLA-I than subtype B Nef sequences. Here we investigated whether Nef amino acids differing in frequency between HIV-1 subtypes B and C explain lower CD4 and HLA-I down-regulation ability of subtype C.FindingsSubtype-specific mutations were introduced into representative subtype B and C Nef sequences and the CD4 and HLA-I down-regulation ability of these mutants was measured by flow cytometry in a CD4+ T cell line. Subtype C consensus 20I and subtype B consensus 20M reduced and increased HLA-I down-regulation respectively, and the S88G immune escape mutation (which is significantly more frequent in subtype C than subtype B) reduced CD4 and HLA-I down-regulation.ConclusionsOur data suggest that these subtype-specific differences may partly contribute to inter-subtype functional differences, and identification of an immune escape mutation – S88G – that impairs Nef function is of relevance to vaccine design.
Highlights
human immunodeficiency virus type 1 (HIV-1) subtype C negative regulation factor (Nef) sequences have a significantly lower ability overall to down-regulate cluster of differentiation 4 (CD4) and human leukocyte antigen (HLA)-I than subtype B Nef sequences
Our data suggest that these subtype-specific differences may partly contribute to inter-subtype functional differences, and identification of an immune escape mutation – S88G – that impairs Nef function is of relevance to vaccine design
Nef performs numerous activities that may contribute to its pathogenic effect, including the down-regulation of CD4 and HLA class I (HLA-I) molecules from the surface of infected cells
Summary
HIV-1 subtype C Nef sequences have a significantly lower ability overall to down-regulate CD4 and HLA-I than subtype B Nef sequences. We directly assessed the effect of subtype-specific mutations at these Nef codons of interest on CD4 and HLA-I down-regulation ability in order to investigate whether these sequence variations contribute to the inter-subtype differences in Nef function.
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