Host-specific adaptation of HIV-1 subtype B in the Japanese population

Abstract

The extent to which HIV-1 clade B strains exhibit population-specific adaptations to host HLA alleles remains incompletely known, in part due to incomplete characterization of HLA-associated HIV-1 polymorphisms (HLA-APs) in different global populations. Moreover, it remains unknown to what extent the same HLA alleles may drive significantly different escape pathways across populations. As the Japanese population exhibits distinctive HLA class I allele distributions, comparative analysis of HLA-APs between HIV-1 clade B-infected Japanese and non-Asian cohorts could shed light on these questions. However, HLA-APs remain incompletely mapped in Japan. In a cohort of 430 treatment-naive Japanese with chronic HIV-1 clade B infection, we identified 284 HLA-APs in Gag, Pol, and Nef using phylogenetically corrected methods. The number of HLA-associated substitutions in Pol, notably those restricted by HLA-B*52:01, was weakly inversely correlated with the plasma viral load (pVL), suggesting that the transmission and persistence of B*52:01-driven Pol mutations could modulate the pVL. Differential selection of HLA-APs between HLA subtype members, including those differing only with respect to substitutions outside the peptide-binding groove, was observed, meriting further investigation as to their mechanisms of selection. Notably, two-thirds of HLA-APs identified in Japan had not been reported in previous studies of predominantly Caucasian cohorts and were attributable to HLA alleles unique to, or enriched in, Japan. We also identified 71 cases where the same HLA allele drove significantly different escape pathways in Japan versus predominantly Caucasian cohorts. Our results underscore the distinct global evolution of HIV-1 clade B as a result of host population-specific cellular immune pressures.

Importance: Cytotoxic T lymphocyte (CTL) escape mutations in HIV-1 are broadly predictable based on the HLA class I alleles expressed by the host. Because HLA allele distributions differ among worldwide populations, the pattern and diversity of HLA-associated escape mutations are likely to be somewhat distinct to each race and region. HLA-associated polymorphisms (HLA-APs) in HIV-1 have previously been identified at the population level in European, North American, Australian, and African cohorts; however, large-scale analyses of HIV-1 clade B-specific HLA-APs in Asians are lacking. Differential intraclade HIV-1 adaptation to global populations can be investigated via comparative analyses of HLA-associated polymorphisms across ethnic groups, but such studies are rare. Here, we identify HLA-APs in a large Japanese HIV-1 clade B cohort using phylogenetically informed methods and observe that the majority of them had not been previously characterized in predominantly Caucasian populations. The results highlight HIV's unique adaptation to cellular immune pressures imposed by different global populations.

FIG 1

Escape map of HLA-APs for Gag, Pol, and Nef in the Japanese cohort. The escape maps indicate the locations, specific residues, and HLA restrictions of HLA-APs (all q < 0.2). The global HIV-1 clade B consensus amino acid sequence is used as a reference. The shaded vertical bars separate blocks of 10 amino acids. Adapted amino acids (those significantly overrepresented in the presence of a given HLA allele) are red. Nonadapted amino acids (those significantly underrepresented in the presence of a given HLA allele) are blue. Polymorphisms associated with the same HLA allele that occur in proximity to one another are grouped together in yellow boxes. A list of all HLA-APs is provided in Table S1 in the supplemental material.

FIG 2

Correlations between HLA-associated substitutions in Gag, Pol, and Nef and viral load or CD4 count. The total number of HLA-associated substitutions in each subject's Gag, Pol, and Nef sequence was determined (see Materials and Methods). (A) Correlation between the number of HLA-associated substitutions in Gag, Pol, or Nef and pVL or CD4 count. (B) Correlation between pVL and the number of HLA-associated substitutions in Pol, with HLA-B*52:01-associated substitutions excluded. (C) Correlation between pVL and the number of HLA-B*52:01-associated substitutions in Pol (all patients). (D) Correlation between the number of HLA-B*52:01-associated substitutions in Pol in HLA-B*52:01-positive individuals (left) and HLA-B*52:01-negative individuals (right). Analyses were performed using Spearman's correlation. Linear regression lines are included in the plots.

FIG 3

Polymorphic positions in HLA class I molecules and differential escape between pairs of HLA subtypes. In each ribbon diagram depicting the HLA-peptide-binding groove, the locations of residues differing among subtype members of the HLA-A*26 (A), HLA-C*03 (B), and HLA-C*14 (C) allele groups are highlighted in red and labeled with their locations and amino acids. HLA-AP comparisons between subtype members are shown in the corresponding plot below. The horizontal bars represent the lnORs, with colors indicating the restricting allele. Infinite lnORs are set to values of ±4. Boldface type indicates HLA-APs whose strengths of selection are statistically significantly different between the two subtype members (P < 0.05; q < 0.2). a.a., amino acid.

FIG 4

Locations of HLA-associated sites common to HIV-1 clade B-infected Japanese and Caucasian cohorts and those unique to Japan. The locations of all HLA-APs in Gag (500 codons), Pol (1,003 codons), and Nef (206 codons) are illustrated. The residues in the Pol TF protein were not analyzed in the IHAC cohort and are thus excluded (gray bar). The blue squares identify codons that harbored at least one HLA-AP in both Japanese and IHAC cohorts. The red squares indicate codons that harbored HLA-APs in Japan but that were not associated with any HLA alleles in the IHAC cohort.

FIG 5

HLA-APs displaying significantly different strengths of selection between Japanese and IHAC cohorts. A phylogenetically corrected interaction test was used to compare the lnOR of selection of HLA-APs in the Japanese cohort versus the IHAC cohort. Comparisons with a P value of <0.01 and a q value of <0.05 are shown. The bars represent the lnORs. Infinite lnORs are set to values of ±4. Boldface type indicates HLA-APs that display diametrically opposed directions of selection between the cohorts (defined here as lnORs of association that were positive in one cohort but negative in the other, where the cohort-specific P values were <0.05 in both cases). A complete list of all comparisons with a P value of <0.05 is available in Table S3 in the supplemental material.

FIG 6

HLA-APs identified as being under differential strengths of selection in Japanese and IHAC cohorts. At a P value of <0.01 and a q value of <0.05, a total of 71 HLA-APs were identified as being under significantly different strengths of selection in the Japanese and IHAC cohorts. (A) Restricting HLA alleles and their HIV-1 protein locations. (B) Numbers of differentially selected HLA-APs, broken down by HLA locus and HIV-1 protein.