Stefan Tenzer 1 , Hayley Crawford 2 , 3 , Phillip Pymm 2 , 3 , Robert Gifford 4 , Vattipally B. Sreenu 2 , Mirjana Weimershaus 5 , Tulio de Oliveira 6 , 7 , Anne Burgevin 5 , Jan Gerstoft 8 , Nadja Akkad 1 , Daniel Lunn 9 , Lars Fugger 2 , 3 , John Bell 10 , Hansjörg Schild 1 , Peter van Endert 5 , Astrid K.N. Iversen 2 , 3 , ∗
24 April 2014
The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8 + T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ∼30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ∼60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.
HLA class I variants drive selection pressures on Gag to limit epitope production
The strength of the selective pressure is positively correlated to HLA frequencies
HIV adaptation to limit epitope production occurs at subtype-specific HIV motifs
HIV adapts in a predictable way to HLA frequencies in newly infected populations
CD8 + T cell responses against HIV-1 effectively delay disease progression in a minority of patients with relatively rare HLA variants but are ineffective in most. Here, Tenzer et al. identify fundamental HIV-1 adaptation to the conserved human antigen-processing machinery that feeds epitopes to HLA. This adaptation occurs at subtype-specific motifs, facilitates subtype diversification, is predictable, and results in CD8 epitope abundances that correlate inversely with the HLA allele frequencies in affected populations. Thus, HIV vaccine immunogenicity might be increased by unnatural substitutions at subtype-specific motifs.