Weaker HLA footprints on HIV in the unique and highly genetically admixed host population of Mexico

HIV circumvents HLA class I-restricted CD8+ T-cell responses through selection of escape mutations that leave characteristic mutational “footprints,” also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive individuals from Mexico and 1,641 individuals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of <0.2, 358 HAPs (201 in Gag, 157 in PR-RT) were identified in Mexico, while 905 (534 in Gag and 371 in PR-RT) were identified in Canada/United States. HAPs identified in Mexico included both canonical HLA-associated escape pathways and novel associations, in particular with HLA alleles enriched in Amerindian and mestizo populations. Remarkably, HLA footprints on HIV in Mexico were not only fewer but also, on average, significantly weaker than those in Canada/United States, although some exceptions were noted. Moreover, exploratory analyses suggested that the weaker HLA footprint on HIV in Mexico may be due, at least in part, to weaker and/or less reproducible HLA-mediated immune pressures on HIV in this population. The implications of these differences for natural and vaccine-induced anti-HIV immunity merit further investigation

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

Progressive ductile shearing during till accretion within the deforming bed of a palaeo-ice stream

This paper presents the results of a detailed microstructural study of a thick till formed beneath the Weichselian (Devensian) Odra palaeo-ice stream, west of Środa Wielkopolska, Poland. This SE-flowing ice stream was one of a number of corridors of faster flowing ice which drained the Scandinavian Ice Sheet in the Baltic region. Macroscopically, the massive, laterally extensive till which formed the bed of this ice stream lacks any obvious evidence of glaciotectonism (thrusting, folding). However, microscale analysis reveals that bed deformation was dominated by foliation development, recording progressive ductile shearing within a subhorizontal subglacial shear zone. Five successive generations of clast microfabric (S1 to S5) have been identified defining a set of up-ice and down-ice dipping Riedel shears, as well as a subhorizontal shear foliation coplanar to the ice-bed interface. Cross-cutting relationships between the shear fabrics record temporal changes in the style of deformation during this progressive shear event. Kinematic indicators (S-C and ECC-type fabrics) within the till indicate a consistent SE-directed shear sense, in agreement with the regional ice flow pattern. A model of bed deformation involving incremental progressive simple shear during till accretion is proposed. The relative age of this deformation was diachronous becoming progressively younger upwards, compatible with subglacial shearing having accompanied till accretion at the top of the deforming bed. Variation in the relative intensity of the microfabrics records changes in the magnitude of the cumulative strain imposed on the till and the degree of coupling between the ice and underlying bed during fast ice flow

A simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase

Background. Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)–B*5701 allele; however, the cost of routine high-resolution HLA typing before initiation of therapy remains prohibitive. We propose a simple approach to reduce B*5701-associated abacavir hypersensitivity based on the screening of human immunodeficiency virus (HIV) reverse transcriptase (RT) for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245. Methods. The correlation between HLA-B*5701 and RT codon 245 variation was investigated in 392 HIV-infected, antiretroviral-naive adults who were initiating highly active antiretroviral therapy. The relationship between codon 245 variation and premature abacavir discontinuation was investigated in a larger cohort of treated individuals (n = 982). Associations between HLA-B*5701 and codon 245 variants were determined using Fisher's exact test or the χ2 test. Results. A very strong association between HLA-B*5701 and RT codon 245 variation was observed. Only 1 (4.2%) of 24 subjects with B*5701 harbored virus with the clade B “wild-type” amino acid 245V, compared with 278 (75.5%) of 368 who did not have B*5701 (P < .001). The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75%, respectively, and the positive and negative predictive values were 20% and 99.6%, respectively. This association remained robust even after antiretroviral treatment was administered (negative predictive value, 100%; n = 269). In abacavir-treated individuals (n = 982), codon 245 substitutions were predictive of premature abacavir discontinuation (P = .02). Conclusions. As HIV RT sequence is incidentally obtained as a part of routine drug-resistance testing, the examination of sequence variation at RT codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir and/or who could benefit from HLA characterization

HLA class I-associated immune selection pressure drives a major portion of HIV-1 evolution in early infection

No abstract availabl

Relationship between HLA class I-driven evolution in Gag, Pol and Nef and clinical markers of HIV disease: A multi-center collaborative study

No abstract availabl

Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1

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 representedthe 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 responsesmay be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies

Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naive individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a similar to 35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies

Reversion of HLA-Associated Polymorphisms in GAG, POL and NEF during the first year of HIV infection: Sites, Rates and pVL correlations

Background: Replicative fitness costs of CTL escape mutations are suggested by reversion upon transmission to HLA-unmatched hosts, however rates of reversion and the clinical significance of acquired escape mutations remain incompletely characterized. Here we identify the most rapidly reverting codons in Gag, Pol and Nef and correlate the number of HLA-mismatched CTL escape mutations with pVL setpoint. Methods: A list of HLA-associated HIV polymorphisms was predefined in an independent analysis of a large chronic untreated cohort (N>1200). Frequencies and rates of reversion of transmitted HLA-associated Gag/Pol/Nef substitutions in hosts not bearing the given HLA allele were calculated in a longitudinal, untreated, subtype-B-infected cohort (N¼98) identified in acute/ early infection over a median 14 months follow-up. The relationship between the presence of acquired HLA-mismatched polymorphisms and pVL setpoint was investigated using Spearman’s rank correlation. Results: Inferred reversions were observed at 38 (8%), 21 (4%) and 36 (17%) Gag, Pol and Nef codons respectively; the majority (65%) within published CTL epitopes. Reversions within Gag epitopes restricted by protective HLA alleles (B*13, B*51, B*57, B*58) occurred more rapidly than reversions outside these regions (p¼0.02). Among the most rapidly reverting Gag mutations were B*57-associated escape mutations at codons 147 and 242 in the IW9 and TW10 epitopes respectively. We observed no significant correlation between the number of acquired HLA-mismatched CTL escape mutations, and pVL setpoint measured at one year post-infection. No significant differences in pVL were observed when restricting to escape mutations within CTL epitopes, or mutations selected by protective HLA alleles