HIV Control through a Single Nucleotide on the HLA-B Locus

Kløverpris, Henrik N.; Harndahl, Mikkel; Leslie, Alasdair; Carlson, Jonathan M.; Ismail, Nasreen; Stok, Mary van der; Huang, Kuan-Hsiang Gary; Chen, Fabian; Riddell, Lynn; Steyn, Dewald; Goedhals, Dominique; Vuuren, C.V. van; Frater, John; Walker, Bruce D.; Carrington, Mary; Ndung’u, Thumbi; Buus, Søren; Goulder, Philip

doi:10.1128/jvi.01020-12

Cited by 41 publications

(47 citation statements)

References 51 publications

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“…Widespread differential escape is consistent with reported differences in HIV-1 disease progression between HLA alleles differing by as little as 1 amino acid (43,68,86) and also supports the notion that analysis of HLA-associated polymorphisms provides a novel perspective from which to discriminate both quantitative and qualitative differences in HLA-restricted immune responses. Of interest, HLA allele subtype pairs that exhibit the highest level of differential escape were those with the greatest intratype sequence divergence, raising the intriguing hypothesis that differential escape may be a consequence of active positive selection at these loci.…”

Section: Discussionsupporting

confidence: 68%

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Carlson

Brumme

Martin

et al. 2012

J Virol

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104

266

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i 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 represented the 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 responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies. HIV-1 is notorious for its genetic diversity and its ability to adapt to selection pressures (44,87,116). Despite this, within-host HIV-1 evolution in response to antiretroviral (61, 72), host cellular immune (15,50,71,94,95), antibody (46), and vaccine-induced (103) selection pressures occurs along generally predictable mutational pathways (3, 84). Studying these evolutionary pathways can offer insight into the immunopathogenesis of HIV-1 and may help inform the design of immune-based interventions and vaccines.Substantial progress has been made in our understanding of HIV-1's ability to evade human leukocyte antigen (HLA) class I-restricted CD8 ϩ cytotoxic T-lymphocytes (CTL). In particular, application of novel statistical methods (13,25,84) to large population-based data sets of linked host and viral genetic information has facilitated the systematic identification of HLA-associated immune escape and covarying mutations in 20,60,81,99,104), revealing important insights into HIV-1 adaptation to its host. We now appreciate that immune selection represents a major force shaping HIV-1 diversity (3,80,...

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Section: Discussionsupporting

confidence: 68%

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Carlson

Brumme

Martin

et al. 2012

J Virol

Self Cite

104

266

View full text Add to dashboard Cite

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“…DNA for typing was extracted from whole blood using the Puregene DNA isolation kit (Gentra Systems, Minneapolis, MN) according to the manufacturer's instructions. HLA alleles were grouped at the 2-digit resolution level, with the exception of A*68, B*15, whose allotypes have divergent binding motifs (30), and B*58, B*42, and B*35, which were previously reported to exhibit discordant associations with disease progression (31)(32)(33)(34).…”

Section: Methodsmentioning

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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“…The mechanism for this protective effect remains poorly understood (53,54). Viral control is linked to the expression of certain alleles encoding HLA class I molecules (particularly HLA-B*57, HLA-B*27, and HLA-B*5801), which suggests an immunological basis related to the function of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions

Gavlovsky

Tonnerre

Gérard

et al. 2016

The Journal of Immunology

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MHC class I chain–related proteins A and B (MICA and MICB) and UL16-binding proteins are ligands of the activating NKG2D receptor involved in cancer and immune surveillance of infection. Structurally, MICA/B proteins contain an α3 domain, whereas UL16-binding proteins do not. We identified novel alternative splice transcripts for MICA encoding five novel MICA isoforms: MICA-A, -B1, -B2, -C, and -D. Alternative splicing associates with MICA*015 and *017 and results from a point deletion (G) in the 5′ splice donor site of MICA intron 4 leading to exon 3 and exon 4 skipping and/or deletions. These changes delete the α3 domain in all isoforms, and the α2 domain in the majority of isoforms (A, B1, C, and D). Endothelial and hematopoietic cells contained endogenous alternative splice transcripts and isoforms. MICA-B1, -B2, and -D bound NKG2D by surface plasmon resonance and were expressed at the cell surface. Functionally, MICA-B2 contains two extracellular domains (α1 and α2) and is a novel potent agonist ligand for NKG2D. We found that MICA-D is a new truncated form of MICA with weak affinity for NKG2D despite lacking α2 and α3 domains. MICA-D may functionally impair NKG2D activation by competing with full-length MICA or MICA-B2 for NKG2D engagement. Our study established NKG2D binding for recombinant MICA-B1 but found no function for this isoform. New truncated MICA isoforms exhibit a range of functions that may drive unexpected immune mechanisms and provide new tools for immunotherapy.

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HIV Control through a Single Nucleotide on the HLA-B Locus

Cited by 41 publications

References 51 publications

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

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

Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions

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HIV Control through a Single Nucleotide on the HLA-B Locus

Cited by 41 publications

References 51 publications

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

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

Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions

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