Founder Effects in the Assessment of HIV Polymorphisms and HLA Allele Associations

Bhattacharya, Tanmoy; Daniels, Marcus G.; Heckerman, David; Foley, Brian; Frahm, Nicole; Kadie, Carl; Carlson, Jonathan M.; Yusim, Karina; McMahon, Benjamin H.; Gaschen, Brian; Mallal, S.; Mullins, James I.; Nickle, David C.; Herbeck, Joshua T.; Rousseau, Christine; Learn, Gerald H.; Miura, Toshiyuki; Berthou, Christian; Walker, Bruce F.; Korber, Bette T.

doi:10.1126/science.1131528

Cited by 244 publications

(336 citation statements)

References 19 publications

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“…Others have previously used phylogenetic methods to adjust for these potential confounding factors. 5,12 In this study, we addressed this issue by identifying clusters of possibly related sequence and assessing the potential impact of such relatedness by performing analyses stratified by clusters. This approach is based on the notion that within relatively homogeneous clusters of possibly related sequences, the distributions of HLA types should be random.…”

Section: Methodsmentioning

confidence: 99%

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

et al. 2009

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Many hepatitis C virus (HCV) infections worldwide are with the genotype 1 and 3 strains of the virus. Cellular immune responses are known to be important in the containment of HCV genotype 1 infection, and many genotype 1 T cell targets (epitopes) that are presented by host human leukocyte antigens (HLAs) have been identified. In contrast, there is almost no information known about the equivalent responses to genotype 3. Immune escape mechanisms used by HCV include the evolution of viral polymorphisms (adaptations) that abrogate this host-viral interaction. Evidence of HCV adaptation to HLA-restricted immune pressure on HCV can be observed at the population level as viral polymorphisms associated with specific HLA types. To evaluate the escape patterns of HCV genotypes 1 and 3, we assessed the associations between viral polymorphisms and specific HLA types from 187 individuals with genotype 1a and 136 individuals with genotype 3a infection. We identified 51 HLA-associated viral polymorphisms (32 for genotype 1a and 19 for genotype 3a). Of these putative viral adaptation sites, six fell within previously published epitopes. Only two HLA-associated viral polymorphisms were common to both genotypes. In the remaining sites with HLA-associated polymorphisms, there was either complete conservation or no significant HLA association with viral polymorphism in the alternative genotype. This study also highlights the diverse mechanisms by which viral evasion of immune responses may be achieved and the role of genotype variation in these processes. Conclusion: There is little overlap in HLA-associated polymorphisms in the nonstructural proteins of HCV for the two genotypes, implying differences in the cellular immune pressures acting on these viruses and different escape profiles. These findings have implications for future therapeutic strategies to combat HCV infection, including vaccine design.

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Section: Methodsmentioning

confidence: 99%

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

et al. 2009

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“…The peptide binding motifs for a number of class II alleles have been defined (2)(3)(4), but many remain unknown. Among these, DR1401 is of considerable interest because of its association with HLA driven HIV escape (5), protection from type I diabetes (6), and susceptibility to psoriasis vulgaris (7) in certain populations. However, remarkably little has been reported about the peptide binding preferences or epitopes recognized by this allele.…”

Section: Introductionmentioning

confidence: 99%

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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This study identified the peptide-binding motif of HLA-DRB1*1401 (DR1401). First, peptides containing DR1401 restricted epitopes were identified using tetramer guided epitope mapping. Among these, an influenza B peptide was selected for the motif study. After confirming the binding register for this peptide using a set of arginine substitutions, binding affinities were determined for 33 peptides derived from this influenza B sequence with single amino acid substitutions. The DR1401 peptide binding motif was deduced from the relative binding affinities of these peptides and confirmed by structural modeling. Pocket 1 demonstrated a preference for aliphatic anchor residues and methionine. Pocket 4 accommodated methionine and aliphatic residues, but also allowed some polar and charged amino acids. Pocket 6 preferred basic residues but also allowed some polar and aliphatic amino acids. Pocket 9 preferred aliphatic and aromatic amino acids and tolerated some polar residues but excluded all charged residues. Together these preferences define a distinct set of peptides that can be presented by DR1401. The resulting motif was used to verify T cell epitopes within the novel antigenic peptides identified by tetramer guided epitope mapping and within peptides from published reports that contain putative DR1401 epitopes.

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“…Nineteen of the associations were located within epitopes previously reported for the HLA and listed in the HIV molecular immunology database of the Los Alamos National Laboratory (LANL) [http://www.hiv.lanl.gov/content/immunology/tables/tables.html], two are with HLA alleles which are in strong linkage disequilibrium with an allele included in the list of reported associations together with the same residue, and a further two have been identified as significant by other correction methods including those using clustering or phylogenetic trees (Bhattacharya et al, 2007. Additionally, we observed 4 associations with PCA-FP p-values <0.001 but large Fisher p-values.…”

Section: Applicationmentioning

confidence: 99%

“…As the virus is transmitted from host to host, any sample taken from a population may include multiple recipients infected by a single donor, or both the donor and recipient of a transmission event, and these related sequences may share random patterns of amino acid polymorphisms, termed founder effects, as a consequence of their shared ancestry (Bhattacharya et al, 2007). Where transmission is HLA-associated, these polymorphisms can confound conventional tests of association, such as Fisher"s exact test.…”

Section: Introductionmentioning

confidence: 99%

“…As both virus subtypes (clades) and HLA alleles have distributions influenced by geography and ethnicity, viral transmission cannot generally be assumed to be independent of HLA type, and so the confounding potential of founder effects must be addressed. A number of model-based methods utilising inferred phylogenetic trees estimated from the observed viral sequences have been proposed and used to correct for this confounding (eg Bhattacharya et al, 2007, Brumme et al, 2009, John et al, 2010. However, the methods are typically very computationally intensive and generally require specialist software for implementation.…”

Section: Introductionmentioning

confidence: 99%

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Correction for Founder Effects in Host-Viral Association Studies via Principal Components

Reeves

McKinnon²,

James³

2012

Statistical Applications in Genetics and Molecular Biology

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Viruses such as HIV and Hepatitis C (HCV) replicate rapidly and with high transcription error rates, which may facilitate their escape from immune detection through the encoding of mutations at key positions within human leukocyte antigen (HLA)-specific peptides, thus impeding T-cell recognition. Large-scale population-based host-viral association studies are conducted as hypothesis-generating analyses which aim to determine the positions within the viral sequence at which host HLA immune pressure may have led to these viral escape mutations. When transmission of the virus to the host is HLA-associated, however, standard tests of association can be confounded by the viral relatedness of contemporarily circulating viral sequences, as viral sequences descended from a common ancestor may share inherited patterns of polymorphisms, termed 'founder effects'. Recognizing the correspondence between this problem and the confounding of case-control genome-wide association studies by population stratification, we adapt methods taken from that field to the analysis of host-viral associations. In particular, we consider methods based on principal components analysis within a logistic regression framework motivated by alternative formulations in the Frisch-Waugh-Lovell Theorem. We demonstrate via simulation their utility in detecting true host-viral associations whilst minimizing confounding by associations generated by founder effects. The proposed methods incorporate relatively robust, standard statistical procedures which can be easily implemented using widely available software, and provide alternatives to the more complex computer intensive methods often implemented in this area.

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Founder Effects in the Assessment of HIV Polymorphisms and HLA Allele Associations

Cited by 244 publications

References 19 publications

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

Correction for Founder Effects in Host-Viral Association Studies via Principal Components

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