Dataset Information

SampPick: Selection of a Cohort of Subjects Matching a Population HLA Distribution.

ABSTRACT: Immune responses to therapeutic proteins and peptides can adversely affect their safety and efficacy; consequently, immunogenicity risk-assessments are part of the development, licensure and clinical use of these products. In most cases the development of anti-drug antibodies is mediated by T cells which requires antigen presentation by Major Histocompatibility Complex Class II (MHCII) molecules (also called Human Leucocyte Antigen, HLA in humans). Immune responses to many protein therapeutics are thus HLA-restricted and it is important that the distribution of HLA variants used in the immunogenicity assessments provides adequate coverage of the target population. Due to biases inherent to the collection of samples in a blood bank or donor pool, simple random sampling will not achieve a truly representative sample of the population of interest. To help select a donor cohort we introduce SampPick, an implementation of simulated annealing which optimizes cohort selection to closely match the frequency distribution of a target population or subpopulation. With inputs of a target background frequency distribution for a population and a set of available, HLA-typed donors, the algorithm will iteratively create a cohort of donors of a user selected size that will closely match the target population rather than a random sample. In addition to optimizing the HLA types of donor cohorts, the software presented can be used to optimize donor cohorts for any other biallelic or monoallelic trait.

SUBMITTER: McGill JR

PROVIDER: S-EPMC6933600 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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SampPick: Selection of a Cohort of Subjects Matching a Population HLA Distribution.

McGill Joseph R JR Yogurtcu Osman N ON Verthelyi Daniela D Yang Hong H Sauna Zuben E ZE

Frontiers in immunology 20191220

Immune responses to therapeutic proteins and peptides can adversely affect their safety and efficacy; consequently, immunogenicity risk-assessments are part of the development, licensure and clinical use of these products. In most cases the development of anti-drug antibodies is mediated by T cells which requires antigen presentation by Major Histocompatibility Complex Class II (MHCII) molecules (also called Human Leucocyte Antigen, HLA in humans). Immune responses to many protein therapeutics a ...[more]

PMID: 31921155

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Project description:Previous studies have demonstrated that effective cytotoxic T lymphocyte (CTL) responses drive the selection of escape mutations that reduce viral replication capacity (VRC). Escape mutations, including those with reduced VRC, can be transmitted and accumulate in a population. Here we compared two antiretroviral therapy (ART)-naive HIV clade B-infected cohorts, in Mexico and Barbados, in which the most protective HLA alleles (HLA-B*27/57/58:01/81:01) are differentially expressed, at 8% and 34%, respectively. Viral loads were significantly higher in Mexico than in Barbados (median, 40,774 versus 14,200; P < 0.0001), and absolute CD4(+) T-cell counts were somewhat lower (median, 380/mm(3) versus 403/mm(3); P = 0.007). We tested the hypothesis that the disparate frequencies of these protective HLA alleles would be associated with a higher VRC at the population level in Mexico. Analysis of VRC in subjects in each cohort, matched for CD4(+) T-cell count, revealed that the VRC was indeed higher in the Mexican cohort (mean, 1.13 versus 1.03; P = 0.0025). Although CD4 counts were matched, viral loads remained significantly higher in the Mexican subjects (P = 0.04). This VRC difference was reflected by a significantly higher frequency in the Barbados cohort of HLA-B*27/57/58:01/81:01-associated Gag escape mutations previously shown to incur a fitness cost on the virus (P = 0.004), a difference between the two cohorts that remained statistically significant even in subjects not expressing these protective alleles (P = 0.01). These data suggest that viral set points and disease progression rates at the population level may be significantly influenced by the prevalence of protective HLA alleles such as HLA-B*27/57/58:01/81:01 and that CD4 count-based guidelines to initiate antiretroviral therapy may need to be modified accordingly, to optimize the effectiveness of treatment-for-prevention strategies and reduce HIV transmission rates to the absolute minimum.Immune control of HIV at an individual level is strongly influenced by the HLA class I genotype. HLA class I molecules mediating effective immune control, such as HLA-B*27 and HLA-B*57, are associated with the selection of escape mutants that reduce viral replicative capacity. The escape mutants selected in infected patients can be transmitted and affect the viral load and CD4 count in the recipient. These findings prompt the hypothesis that the frequency of protective alleles in a population may affect viral set points and rates of disease progression in that population. These studies in Mexico and Barbados, where the prevalence rates of protective HLA alleles are 8% and 34%, respectively, support this hypothesis. These data suggest that antiretroviral therapy (ART) treatment-for-prevention strategies will be less successful in populations such as those in Mexico, where viral loads are higher for a given CD4 count. Consideration may therefore usefully be given to ART initiation at higher absolute CD4 counts in such populations to optimize the impact of ART for prevention.

Dataset Information

SampPick: Selection of a Cohort of Subjects Matching a Population HLA Distribution.

Publications

SampPick: Selection of a Cohort of Subjects Matching a Population HLA Distribution.

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