Evolution and transmission of stable CTL escape mutations in HIV infection

Abstract

Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

“…Under selection pressure from the immune system, HIV-1 also mutates rapidly to evade cytotoxic T lymphocyte responses. These epitopecentric escape mutations typically alter the conformation of exposed residues that interact with the T-cell receptor 50,51,52,53 or abrogate peptide presentation via effects on antigen processing or HLA-I binding 54,55 . Here, we report a novel mode of escape whereby the common T3N mutant exploits the P-1 overhang of TW10 and the anchor residue preferences in the A and B pockets to shift the register of the peptide within HLA-B*57:01.…”

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

“…Indeed HIV has been shown to escape from CTL immune surveillance by mutation at P2 [3,30], and this escape is mediated by immune selection pressure [31,32]. The viral capsid interactions between two neighboring p24 molecules are mediated by residues within the HIV epitope, and it appears that modification of the P6 leucine to methionine permits mutation of the P2 arginine without significant loss of viral fitness [31].…”

“…or coincidentally with, mutation of the P2 arginine to threonine, lysine or aspartate [31,32]. Studies have shown that the M6 mutant retains full binding potential to the HLA-B*2705 groove [30,31], and the HLA-B*2705-HIV structure indicates that the P6 leucine side chain, being solvent-exposed, plays little role in stabilizing the HIV epitope's binding to HLA-B*2705.…”

Cellular immune responses against hepatitis C virus: the evidence base 2002

“…If escape occurs in variable viruses, it is highly epitope dependent, as is clear from detailed studies of HLA-B27-restricted epitopes in HIV [71][72][73]. Some of these epitopes may fall in regions that are 'constrained' or stable within the virus, due to conserved structure or function and multiple 'compensatory' mutations may need to accumulate, which does not occur readily.…”