Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

McKinnon, Lyle R.; Capiña, Rupert; Peters, Harold O.; Mendoza, Mark; Kimani, Joshua; Wachihi, Charles; Kariri, Anthony; Kimani, Makobu; Richmond, Meika; Kiazyk, Sandy Koesters; Fowke, Keith R.; Jaoko, Walter; Luo, Ma; Ball, T. Blake; Plummer, Francis A.

doi:10.1128/jvi.01236-09

Cited by 15 publications

(15 citation statements)

References 49 publications

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“…Adding an additional wrinkle to this analysis is a recent report indicating a relationship between HIV-1 clade-specific viral polymorphisms and HLA class I alleles [100].…”

Section: Reviewmentioning

confidence: 99%

Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS

Ahlers¹,

Belyakov

2010

Trends in Immunology

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“…Adding an additional wrinkle to this analysis is a recent report indicating a relationship between HIV-1 clade-specific viral polymorphisms and HLA class I alleles [100].…”

Section: Reviewmentioning

confidence: 99%

Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS

Ahlers¹,

Belyakov

2010

Trends in Immunology

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“…For example, HLA-B*57/58:01-driven escape in KF11 (Gag codons 162 to 172) occurs via A163G in subtype C but S173T in subtype B, as the former compromises viral replication in a subtype B backbone (38,39); similarly, M250I, located one codon downstream of TW10 (Gag codons 240 to 249), is readily selected in subtype C but only rarely in subtype B, where it attenuates viral replication (40). Differential HLA-B*57-associated escape within the KF11, IW9 (Gag 147 to 155), and TW10 epitopes has also been described between subtypes A1 and D, though the underlying mechanisms remain to be elucidated (41,42). A framework to identify viral regions that differ in immunogenicity between HIV subtypes or where the functional costs of immune escape differ between HIV subtypes could thus aid in vaccine design.…”

mentioning

confidence: 99%

“…HIV subtype-specific functional constraints underlie some instances of differential escape: B*57:03-Gag T242N. Gag TW10 is strongly and frequently recognized by B*57-expressing individuals infected with various HIV subtypes (15,50,52), including A1 and D (41,53). However, whereas Gag T242N is reproducibly selected by B*57:03 in subtype D (and others [9,45]), it is not selected by this allele in subtype A1 ( Fig.…”

mentioning

confidence: 99%

Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity

Kinloch

Lee

Carlson

et al. 2019

J Virol

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The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol, and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies. IMPORTANCE The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.

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“…The subtype of HLA-B*57 most prevalent in sub-Saharan Africa, the region worst affected by the global HIV epidemic, is HLA-B*5703, which is the allele associated with the lowest viral loads in the region (11,27,29,31,34,41,54). HLA-B*5703 differs by only a single amino acid from the other HLA-B*57 subtype arising at significant levels in these populations, HLA-B*5702 (Leu at HLA residue 156 in HLA-B*5703 and Arg at residue 156 in HLA-B*5702).…”

mentioning

confidence: 99%

HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control

Kløverpris

Stryhn

Harndahl

et al. 2012

J Virol

106

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The genetic polymorphism that has the greatest impact on immune control of human immunodeficiency virus (HIV) infection is expression of HLA-B*57. Understanding of the mechanism for this strong effect remains incomplete. HLA-B*57 alleles and the closely related HLA-B*5801 are often grouped together because of their similar peptide-binding motifs and HIV disease outcome associations. However, we show here that the apparently small differences between HLA-B*57 alleles, termed HLA-B*57 micropolymorphisms, have a significant impact on immune control of HIV. In a study cohort of >2,000 HIV C-clade-infected subjects from southern Africa, HLA-B*5703 is associated with a lower viral-load set point than HLA-B*5702 and HLA-B*5801 (medians, 5,980, 15,190, and 19,000 HIV copies/ml plasma; P ‫؍‬ 0.24 and P ‫؍‬ 0.0005). In order to better understand these observed differences in HLA-B*57/5801-mediated immune control of HIV, we undertook, in a study of >1,000 C-clade-infected subjects, a comprehensive analysis of the epitopes presented by these 3 alleles and of the selection pressure imposed on HIV by each response. In contrast to previous studies, we show that each of these three HLA alleles is characterized both by unique CD8 ؉ T-cell specificities and by clear-cut differences in selection pressure imposed on the virus by those responses. These studies comprehensively define for the first time the CD8 ؉ T-cell responses and immune selection pressures for which these protective alleles are responsible. These findings are consistent with HLA class I alleles mediating effective immune control of HIV through the number of p24 Gag-specific CD8 ؉ T-cell responses generated that can drive significant selection pressure on the virus.

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Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

Cited by 15 publications

References 49 publications

Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS

Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS

Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity

HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control

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