Trachtenberg, E. Advantage of rare HLA supertype in HIV disease progression. Nat. Med. 9, 930-937

Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way Oakland, California 94609, USA.
Nature Medicine (Impact Factor: 27.36). 08/2003; 9(7):928-35. DOI: 10.1038/nm893
Source: PubMed


The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

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Available from: Kevin J Kunstman, Oct 05, 2015
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    • "In subsequent assays, peptide #20 should be tested separately along with shorter, amino-and carboxy-terminally truncated peptides to determine the minimal optimal epitope within the 15mer. beneficial effects, i.e., lower viral titers and slower disease progression in HIV infection (Trachtenberg et al., 2003). Of note, HLA- B ⁄ 2701 is also associated with autoimmune diseases such as ankylosing spondylitis, which suggests that it may present self antigens and contribute to loss of tolerance against these antigens (Lopez de Castro, 2005). "
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    • "While these findings clearly need to be confirmed in additional studies performed in cohorts with differential ethnical backgrounds, they indicate that vaccine candidates that have been designed considering HLA class I prototypes only may exclude protective CD8+ T cell epitopes restricted by minor HLA subtypes. In this scenario, it is important to note that rare HLA types and subtypes may predominantly contribute to viral control [23]. "
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    ABSTRACT: HLA-B∗27 is associated with spontaneous HCV genotype 1 clearance. HLA-B∗27-restricted CD8+ T-cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B∗27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B∗27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B∗27+ patients with chronic HCV genotype 1 infection. CD8+ T-cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B∗27:02 and 05. The NS5B2820 epitope is only restricted by the HLA-B∗27 subtype HLA-B∗27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B∗27 subtype B∗27:05. Indeed, the epitope is very dominant in HLA-B∗27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B∗27:02+ chronically infected patients. The NS5B2820 epitope is immunodominant in the context of HLA-B∗27:02, but is not restricted by other HLA-B∗27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines. (250/250).
    Journal of Hepatology 08/2013; 60(1). DOI:10.1016/j.jhep.2013.08.009 · 11.34 Impact Factor
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    • "Conversely to the association between HLA-B*57 and lower CrNA titers, the HLA-B*07 allele was more prevalent among individuals with higher titers of CrNA, although not significant after correction for multiple testing. Interestingly, HLA-B*07, which is part of the HLA-B7 supertype, is more prevalent among HIV-1 infected individuals who experience a more rapid disease progression and a higher viral load at set-point [34]. The higher prevalence of a non-protective HLA-B type and the lower prevalence of protective HLA-B types in individuals with higher CrNA titers fit the observations that CrNA does not protect from HIV-1 disease progression [2], [8]. "
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    ABSTRACT: Broadly neutralizing antibodies may protect against HIV-1 acquisition. In natural infection, only 10-30% of patients have cross-reactive neutralizing humoral immunity which may relate to viral and or host factors. To explore the role of host genetic markers in the formation of cross-reactive neutralizing activity (CrNA) in HIV-1 infected individuals, we performed a genome-wide association study (GWAS), in participants of the Amsterdam Cohort Studies with known CrNA in their sera. Single-nucleotide polymorphisms (SNPs) with the strongest P-values are located in the major histocompatibility complex (MHC) region, close to MICA (P = 7.68×10(-7)), HLA-B (P = 6.96×10(-6)) and in the coding region of HCP5 (P = 1.34×10(-5)). However, none of the signals reached genome-wide significance. Our findings underline the potential involvement of genes close or within the MHC region with the development of CrNA.
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