Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Abstract

i HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies. HIV-1 is notorious for its genetic diversity and its ability to adapt to selection pressures (44,87,116). Despite this, within-host HIV-1 evolution in response to antiretroviral (61, 72), host cellular immune (15,50,71,94,95), antibody (46), and vaccine-induced (103) selection pressures occurs along generally predictable mutational pathways (3, 84). Studying these evolutionary pathways can offer insight into the immunopathogenesis of HIV-1 and may help inform the design of immune-based interventions and vaccines.Substantial progress has been made in our understanding of HIV-1's ability to evade human leukocyte antigen (HLA) class I-restricted CD8 ϩ cytotoxic T-lymphocytes (CTL). In particular, application of novel statistical methods (13,25,84) to large population-based data sets of linked host and viral genetic information has facilitated the systematic identification of HLA-associated immune escape and covarying mutations in 20,60,81,99,104), revealing important insights into HIV-1 adaptation to its host. We now appreciate that immune selection represents a major force shaping HIV-1 diversity (3,80,...

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

“…HLA-associated polymorphisms derived from the International HIV Adaptation Collaborative (IHAC) cohort, comprising 1,888 treatmentnaive individuals with chronic clade B infection from Canada, the United States, and Western Australia (16), identified by identical methods, were used for comparison. The IHAC cohort comprises predominantly Caucasian individuals, with Asians making up less than 5% of the total.…”

“…HLA-APs can be identified in large cross-sectional linked data sets of host (HLA) and HIV genotypes using statistical-association approaches that identify viral polymorphisms significantly over-or underrepresented in individuals harboring a specific HLA class I allele (1,2,4,(16)(17)(18)21). HLA-APs that are overrepresented in individuals harboring the relevant HLA are commonly referred to as "adapted" forms, while those underrepresented in individuals harboring the relevant HLA are referred to as "nonadapted" forms (2,18).…”

“…As such, "nonadapted" and "adapted" forms can be conceptualized to represent the "immunologically susceptible" and "escape mutant" forms, respectively, for the specific HLA allele in question at that HIV codon position. Statistical association approaches for the identification of HLA-APs also correct for the confounding influences of viral phylogeny, HIV codon covariation, and linkage disequilibrium (LD) between HLA class I alleles (2,16,17,21).…”

“…First, the identification of HLA-APs must be undertaken at the HLA subtype level. This is because the majority (Ͼ60%) of HLA-associated polymorphisms are best defined at the subtype level (16), even for closely related HLA subtype members that present the same or similar peptide epitopes (16,17,18,19). Comparative studies undertaken at allele level (two-digit) resolution cannot disentangle whether population-specific HLA-APs are attributable to differential HLA subtype distributions between cohorts or whether they are "true" cases where the same HLA subtype drives different escape pathways across populations.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…In addition, the presence of variable epitopes in immunogens encompassing the native proteins can result in immunodominance (i.e., hierarchical recognition of some epitopes in the vaccine over others) with the generation of immunodominant T cell responses targeting non-protective epitopes that do not contribute significantly to viral control and can easily mutate without impairing viral fitness, and facilitating the propagation of functionally fit escape mutants. HLA represents a major force driving the evolution and diversification of HIV-1 within individuals and at the population level 26–28 with recognition of immunodominant but non-protective epitopes. It has been suggested that variable sequences can serve as immunodominant “decoys” that can absorb immune reactivity, driving the emergence of escape mutations and potentially precluding responses against conserved protective epitopes.…”