Evolutionary Principles in Viral Epitopes
The infection of a cell by a virus elicits a Cytotoxic T Lymphocyte (CTL) response to viral peptides presented by the Major Histocompatibility Complex class I molecules [6, 20]. Such a CTL response plays a critical role in the host’s anti-viral immune res
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1 Introduction: Can We Learn from Epitope Distribution on Viral Evolution? The infection of a cell by a virus elicits a Cytotoxic T Lymphocyte (CTL) response to viral peptides presented by the Major Histocompatibility Complex class I molecules [6, 20]. Such a CTL response plays a critical role in the host’s antiviral immune response [39]. This role is suggested by studies indicating a drop of viral loads and the relief of the acute infection symptoms following the emergence of virus-specific CTLs [8], as well as by data from CTL depleted animal models [33, 41]. The CTL response is also associated with a rapid selection of viral CTL escape variants [23, 34]. In the last few years we have applied an immunomic methodology combining genomic data and multiple bioinformatic tools to study the anti-viral CTL response [5, 19, 28, 35, 38, 55–57] and found that viruses selectively mutate proteins inducing the highest danger to their survival. We here summarize these results, and propose some general conclusions regarding the selective forces affecting viruses and their human host. In general, CTL epitopes are short peptides that can be recognized by CTLs when presented on MHC-I molecules, as will be further explained. These epitopes originate from short peptides cleaved by the proteasome [48] that can pass through the transporter associated with antigen processing (TAP) and associate non-covalently with the groove of MHC-I molecules. A large fraction of these
Y. Maman The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 52900 Israel A. Agranovich • T.V. Shalit • Y. Louzoun () Department of Mathematics and Gonda Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel e-mail: [email protected] U. Ledzewicz et al., Mathematical Methods and Models in Biomedicine, Lecture Notes on Mathematical Modelling in the Life Sciences, DOI 10.1007/978-1-4614-4178-6 3, © Springer Science+Business Media New York 2013
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epitopes are nine-mers (although 8-mers, 10-mers and even longer epitopes are also observed). A cleaved nine-mer is presented on an MHC-I molecule only if its affinity to the MHC molecule is sufficiently high. Normally, MHC-I molecules present fragments originated from cellular proteins. After viral infection, virusoriginated peptides are presented on these molecules, enabling immune recognition of the virus [6]. We have recently developed and improved a set of bioinformatic tools to estimate all peptides within a virus that can be presented to the immune system (the CTL epitope repertoire) [54]. The human leukocyte antigen (HLA) locus, the locus that encodes the MHC molecules in human, is the most polymorphic locus in the human genome. In the class I locus HLA-A, B and C have over 2,000 reported alleles, and their number keeps increasing [47]. This large polymorphism permits a rapid selection of alleles that can respond to viral threats. On the other hand, viruses can mutate rapidly. For example, the human immunodeficiency virus (HIV) mutation rate i
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