A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Bartha, István; Carlson, Jonathan M.; Brumme, Chanson J.; McLaren, Paul J.; Brumme, Zabrina L.; John, Mina; Haas, David W.; Martínez-Picado, Javier; Dalmau, Judith; López-Galı́ndez, Cecilio; Casado, Concepción; Rauch, Andri; Günthard, Huldrych F.; Bernasconi, Enos; Vernazza, Pietro; Klimkait, Thomas; Yerly, Sabine; O’Brien, Stephen J.; Listgarten, Jennifer; Pfeifer, Nico; Lippert, Christoph; Fusi, Nicoló; Kutalik, Zoltán; Allen, Todd M.; Müller, Viktor; Harrigan, P. Richard; Heckerman, David; Telenti, Amalio; Fellay, Jacques

doi:10.7554/elife.01123

Cited by 138 publications

(155 citation statements)

References 42 publications

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“…Interestingly, analyses aimed at estimating the viral genetic component of heritability have been generally higher, ∼30-50%, than our estimated host component (24). However, it is difficult to disentangle these two values because host genetic variation, in particular the class I HLA region, exerts substantial pressure on the viral genetic sequence (25). Indeed, if the influence of host and viral genetics highly overlaps, up to an additional 70% of variability in spVL may remain unaccounted for.…”

Section: Discussionmentioning

confidence: 61%

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

McLaren

Coulonges

Bartha

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Previous genome-wide association studies (GWAS) of HIV-1–infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation—mostly in the HLA and CCR5 regions—explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

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Section: Discussionmentioning

confidence: 61%

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

McLaren

Coulonges

Bartha

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

161

190

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“…It is more and more evident that the identification of both virulence factors of the pathogen and susceptibility variants of the host is critical for our understanding of host-pathogen interaction. Joint association analyses of both genomes hold great potential to uncover footprints of natural selection, as shown recently for HIV (52) Progress in the isolation and culture of Borrelia from human serum might soon bring similar approaches within achievable range (53).…”

Section: Resultsmentioning

confidence: 99%

A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity

Hammer

Wanitchakool

Sirianant

et al. 2015

Mol Med

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In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl -channels and phospholipid scram-

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“…If CTL targeting is effective at limiting viral reproduction, then there will be significant selection pressure that will favor viral variants that ameliorate the immune response by, for example, disrupting epitope processing (75)(76)(77), HLA binding (70,78), and/or TcR recognition (79)(80)(81)(82). The importance of such immune escape is suggested by the extent to which specific HIV polymorphisms are correlated with the expression of specific HLA alleles (55,(83)(84)(85), as well as the observation that roughly a third of observed mutations in early infection are consistent with escape or reversion (86).…”

Section: Discussionmentioning

confidence: 99%

HIV Control Is Mediated in Part by CD8 ⁺ T-Cell Targeting of Specific Epitopes

Pereyra

Heckerman

Carlson

et al. 2014

J Virol

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We investigated the hypothesis that the correlation between the class I HLA types of an individual and whether that individual spontaneously controls HIV-1 is mediated by the targeting of specific epitopes by CD8 ؉ T cells. By measuring gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay responses to a panel of 257 optimally defined epitopes in 341 untreated HIV-infected persons, including persons who spontaneously control viremia, we found that the correlation between HLA types and control is mediated by the targeting of specific epitopes. Moreover, we performed a graphical model-based analysis that suggested that the targeting of specific epitopes is a cause of such control-that is, some epitopes are protective rather than merely associated with control-and identified eight epitopes that are significantly protective. In addition, we use an in silico analysis to identify protein regions where mutations are likely to affect the stability of a protein, and we found that the protective epitopes identified by the ELISPOT analysis correspond almost perfectly to such regions. This in silico analysis thus suggests a possible mechanism for control and could be used to identify protective epitopes that are not often targeted in natural infection but that may be potentially useful in a vaccine. Our analyses thus argue for the inclusion (and exclusion) of specific epitopes in an HIV vaccine. IMPORTANCESome individuals naturally control HIV replication in the absence of antiretroviral therapy, and this ability to control is strongly correlated with the HLA class I alleles that they express. Here, in a large-scale experimental study, we provide evidence that this correlation is mediated largely by the targeting of specific CD8 ؉ T-cell epitopes, and we identify eight epitopes that are likely to cause control. In addition, we provide an in silico analysis indicating that control occurs because mutations within these epitopes change the stability of the protein structures. This in silico analysis also identified additional epitopes that are not typically targeted in natural infection but may lead to control when included in a vaccine, provided that other epitopes that would otherwise distract the immune system from targeting them are excluded from the vaccine.

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A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Cited by 138 publications

References 42 publications

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity

HIV Control Is Mediated in Part by CD8 ⁺ T-Cell Targeting of Specific Epitopes

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A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Cited by 138 publications

References 42 publications

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity

HIV Control Is Mediated in Part by CD8 + T-Cell Targeting of Specific Epitopes

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HIV Control Is Mediated in Part by CD8 ⁺ T-Cell Targeting of Specific Epitopes