Escape from the Dominant HLA-B27-Restricted Cytotoxic T-Lymphocyte Response in Gag Is Associated with a Dramatic Reduction in Human Immunodeficiency Virus Type 1 Replication

Abstract

Human leukocyte antigen (HLA)-B27-positive subjects are uncommon in their ability to control infection with human immunodeficiency virus type 1 (HIV-1). However, late viral escape from a narrowly directed immunodominant Gag-specific CD8؉ T-lymphocyte (CTL) response has been linked to AIDS progression in these individuals. Identifying the mechanism of the immune-mediated control may provide critical insights into HIV-1 vaccine development. Here, we illustrate that the CTL escape mutation R 264 K in the HLA-B27-restricted KK10 epitope in the capsid resulted in a significant defect in viral replication in vitro. The R 264 K variant was impaired in generating late reverse transcription products, indicating that replication was blocked at a postentry step. Notably, the R 264 K mutation was associated in vivo with the development of a rare secondary mutation, S 173 A, which restored viral replication in vitro. Furthermore, infectivity of the R 264 K variant was rescued by the addition of cyclosporine A or infection of a cyclophilin A-deficient cell line. These data demonstrate a severe functional defect imposed by the R 264 K mutation during an early step in viral replication that is likely due to the inability of this variant to replicate efficiently in the presence of normal levels of cyclophilin A. We conclude that the impact of the R 264 K substitution on capsid structure constrains viral escape and enables long-term maintenance of the dominant CTL response against B27-KK10, providing an explanation for the protective effect of HLA-B27 during HIV infection.

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.…”

Host-Specific Adaptation of HIV-1 Subtype B in the Japanese Population

“…Protective HLA alleles, such as HLA-B*57, -B*58, and -B*27, select Gag mutations affecting viral replication in Caucasians and Africans (36)(37)(38)(39)(40)(41) that may also provide some clinical benefit if they are transmitted to hosts lacking these alleles (42,43). HLA-B*57, -B*58, and -B*27 are not present at appreciable frequencies in Japan (23).…”

Persistent Survival of Prevalent Clonotypes within an Immunodominant HIV Gag-Specific CD8+ T Cell Response

“…Commonly during early infection, a leucine (L) to methionine (M) substitution occurs at position 6 (L268M); subsequently, an arginine (R) to lysine (K) mutation occurs at position 2 (R264K). Alternative amino acid substitutions at position R264 (G, Q, and T) have also been found at lower frequencies (7)(8)(9). This modification of R264, which acts as an anchor residue within the B-pocket of the HLA-B*2705 molecule, commonly occurs late in the disease process and diminishes epitope presentation through a pronounced reduction in peptide binding affinity (1,(7)(8)(9).…”

“…Importantly, phylogenetic analyses of sequential viral mutations demonstrate that R264K and L268M are independent events (7); this lack of association also suggests that the L268M substitution might constitute a prerequisite for the later R264K immune escape mutation (9), generating a CTL escape virus phenotype that can be stably transferred (2, 10) with fitness levels similar to that of wild-type (WT) virus (11). No current evidence exists to suggest that the L268M mutation affects HLA binding; however, this variant may represent an attempt by the virus to escape from TCR recognition (6,9). Structural analysis of the KK10 peptide bound to HLA-B*2705 indicates that amino acid residue 268 bulges from the binding groove and thus has the potential to interact directly with the TCR (12).…”

“…This modification of R264, which acts as an anchor residue within the B-pocket of the HLA-B*2705 molecule, commonly occurs late in the disease process and diminishes epitope presentation through a pronounced reduction in peptide binding affinity (1,(7)(8)(9). Importantly, phylogenetic analyses of sequential viral mutations demonstrate that R264K and L268M are independent events (7); this lack of association also suggests that the L268M substitution might constitute a prerequisite for the later R264K immune escape mutation (9), generating a CTL escape virus phenotype that can be stably transferred (2, 10) with fitness levels similar to that of wild-type (WT) virus (11). No current evidence exists to suggest that the L268M mutation affects HLA binding; however, this variant may represent an attempt by the virus to escape from TCR recognition (6,9).…”