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.


Available from: Kevin J Kunstman
  • Source
    • "In line with the expectation that supertypes constitute a functionally relevant definition of HLA variation, several researchers have found that grouping alleles into supertypes is useful in disease association studies involving HLA loci (Alencar et al. 2013; Chakraborty et al. 2013; Cordery et al. 2012; Gilchuk et al. 2013; Karlsson et al. 2012, 2013; Kuniholm et al. 2013; Trachtenberg et al. 2003), allowing large numbers of rare alleles to be grouped according to a functional criterion, thus increasing the power of the studies. From an evolutionary point of view, natural selection is expected to leave a detectable signature on B and F pockets and, consequently, on the genotypes defined by examining HLA variation from the perspective of supertypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.
    Immunogenetics 10/2015; 67(11). DOI:10.1007/s00251-015-0875-9 · 2.23 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV)-specific T cells are key factors in the outcome of acute HCV infection and in protective immunity. This review recapitulates the steps that immunologists have taken in the past 25 years to dissect the role of T cell responses in HCV infection. It describes technical as well as disease-specific challenges that were caused by the inapparent onset of acute HCV infection, the difficulty to identify subjects who spontaneously clear HCV infection, the low frequency of HCV-specific T cells in the blood of chronically infected patients, and the lack of small animal models with intact immune systems to study virus-host interaction. The review provides a historical perspective on techniques and key findings, and identifies areas for future research.
    Antiviral Research 11/2014; 114. DOI:10.1016/j.antiviral.2014.11.009 · 3.94 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
Show more