Article

Advantage of rare HLA supertype in HIV disease progression

Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way Oakland, California 94609, USA.
Nature Medicine (Impact Factor: 28.05). 08/2003; 9(7):928-35. DOI: 10.1038/nm893
Source: PubMed

ABSTRACT 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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    • "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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    • "The mechanisms responsible for maintaining polymorphism at MHC genes include negative frequency dependent selection (Snell 1968; Borghans et al. 2004) and heterozygote advantage (Doherty and Zinkernagel 1975), which are not mutually exclusive. Frequency dependence arises because the carriers of common alleles are more likely to be invaded by coevolving parasites while new and thus rather rare MHC alleles cause a temporary advantage (Trachtenberg et al. 2003). Heterozygosity allows presentation of a wider range of pathogen-derived peptides, and thus provides greater resistance to infection (Carrington 1999; Penn et al. 2002). "
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