Abstract
BackgroundStudies have shown that in the genome of human immunodeficiency virus (HIV-1) regions responsible for interactions with the host's immune system, namely, cytotoxic T-lymphocyte (CTL) epitopes tend to cluster together in relatively conserved regions. On the other hand, "epitope-less" regions or regions with relatively low density of epitopes tend to be more variable. However, very little is known about relationships among epitopes from different genes, in other words, whether particular epitopes from different genes would occur together in the same viral genome. To identify CTL epitopes in different genes that co-occur in HIV genomes, association rule mining was used.ResultsUsing a set of 189 best-defined HIV-1 CTL/CD8+ epitopes from 9 different protein-coding genes, as described by Frahm, Linde & Brander (2007), we examined the complete genomic sequences of 62 reference HIV sequences (including 13 subtypes and sub-subtypes with approximately 4 representative sequences for each subtype or sub-subtype, and 18 circulating recombinant forms). The results showed that despite inclusion of recombinant sequences that would be expected to break-up associations of epitopes in different genes when two different genomes are recombined, there exist particular combinations of epitopes (epitope associations) that occur repeatedly across the world-wide population of HIV-1. For example, Pol epitope LFLDGIDKA is found to be significantly associated with epitopes GHQAAMQML and FLKEKGGL from Gag and Nef, respectively, and this association rule is observed even among circulating recombinant forms.ConclusionWe have identified CTL epitope combinations co-occurring in HIV-1 genomes including different subtypes and recombinant forms. Such co-occurrence has important implications for design of complex vaccines (multi-epitope vaccines) and/or drugs that would target multiple HIV-1 regions at once and, thus, may be expected to overcome challenges associated with viral escape.
Highlights
Studies have shown that in the genome of human immunodeficiency virus (HIV-1) regions responsible for interactions with the host's immune system, namely, cytotoxic Tlymphocyte (CTL) epitopes tend to cluster together in relatively conserved regions
In HIV certain CTL epitopes are subjected to consistent selective pressure from the host's immune system, leading to rapid accumulation of amino acid changes, while other CTL epitopes evolve under purifying selection pressure [9,10]
Our results show that some CTL epitopes are significantly associated with each other so that they co-occur together in the majority of the reference viral genomes including circulating recombinant forms
Summary
Studies have shown that in the genome of human immunodeficiency virus (HIV-1) regions responsible for interactions with the host's immune system, namely, cytotoxic Tlymphocyte (CTL) epitopes tend to cluster together in relatively conserved regions. CTL and MHC class I molecules) are an integral – and critical – part of this recognition process, and amino acid changes at CTL epitopes have been shown to play a role in viral "escape" (in other words, evading recognition by the immune system) in human (HIV) and simian (SIV) immunodeficiency viruses [3,4,5,6,7,8]. The epitope-vaccine approach has been suggested as a strategy to circumvent the rapid rate of mutations in HIV1 and the subsequent viral escape from the host's immune system as well as the development of resistance to antiviral drugs [12,13,14]. Likewise, when epitopes from different genes or genomic regions are included in the same vaccine, such multi-epitope vaccines can induce broader cellular immune responses [15,16]
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