Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag.
HIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies ha...
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Public Library of Science (PLoS)
2008-11-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000225&type=printable |
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| author | Jonathan M Carlson Zabrina L Brumme Christine M Rousseau Chanson J Brumme Philippa Matthews Carl Kadie James I Mullins Bruce D Walker P Richard Harrigan Philip J R Goulder David Heckerman |
| author_facet | Jonathan M Carlson Zabrina L Brumme Christine M Rousseau Chanson J Brumme Philippa Matthews Carl Kadie James I Mullins Bruce D Walker P Richard Harrigan Philip J R Goulder David Heckerman |
| author_sort | Jonathan M Carlson |
| collection | DOAJ |
| description | HIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies have been limited by the inability to simultaneously account for HIV codon covariation, linkage disequilibrium among HLA alleles, and the confounding effects of HIV phylogeny when attempting to identify HLA-associated viral evolution. We have developed a statistical model of evolution, called a phylogenetic dependency network, that accounts for these three sources of confounding and identifies the primary sources of selection pressure acting on each HIV codon. Using synthetic data, we demonstrate the utility of this approach for identifying sites of HLA-mediated selection pressure and codon evolution as well as the deleterious effects of failing to account for all three sources of confounding. We then apply our approach to a large, clinically-derived dataset of Gag p17 and p24 sequences from a multicenter cohort of 1144 HIV-infected individuals from British Columbia, Canada (predominantly HIV-1 clade B) and Durban, South Africa (predominantly HIV-1 clade C). The resulting phylogenetic dependency network is dense, containing 149 associations between HLA alleles and HIV codons and 1386 associations among HIV codons. These associations include the complete reconstruction of several recently defined escape and compensatory mutation pathways and agree with emerging data on patterns of epitope targeting. The phylogenetic dependency network adds to the growing body of literature suggesting that sites of escape, order of escape, and compensatory mutations are largely consistent even across different clades, although we also identify several differences between clades. As recent case studies have demonstrated, understanding both the complexity and the consistency of immune escape has important implications for CTL-based vaccine design. Phylogenetic dependency networks represent a major step toward systematically expanding our understanding of CTL escape to diverse populations and whole viral genes. |
| format | Article |
| id | doaj-art-e61b6ed8a25c42d0982ce1e881a1fc15 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2008-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-e61b6ed8a25c42d0982ce1e881a1fc152025-08-20T02:02:44ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582008-11-01411e100022510.1371/journal.pcbi.1000225Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag.Jonathan M CarlsonZabrina L BrummeChristine M RousseauChanson J BrummePhilippa MatthewsCarl KadieJames I MullinsBruce D WalkerP Richard HarriganPhilip J R GoulderDavid HeckermanHIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies have been limited by the inability to simultaneously account for HIV codon covariation, linkage disequilibrium among HLA alleles, and the confounding effects of HIV phylogeny when attempting to identify HLA-associated viral evolution. We have developed a statistical model of evolution, called a phylogenetic dependency network, that accounts for these three sources of confounding and identifies the primary sources of selection pressure acting on each HIV codon. Using synthetic data, we demonstrate the utility of this approach for identifying sites of HLA-mediated selection pressure and codon evolution as well as the deleterious effects of failing to account for all three sources of confounding. We then apply our approach to a large, clinically-derived dataset of Gag p17 and p24 sequences from a multicenter cohort of 1144 HIV-infected individuals from British Columbia, Canada (predominantly HIV-1 clade B) and Durban, South Africa (predominantly HIV-1 clade C). The resulting phylogenetic dependency network is dense, containing 149 associations between HLA alleles and HIV codons and 1386 associations among HIV codons. These associations include the complete reconstruction of several recently defined escape and compensatory mutation pathways and agree with emerging data on patterns of epitope targeting. The phylogenetic dependency network adds to the growing body of literature suggesting that sites of escape, order of escape, and compensatory mutations are largely consistent even across different clades, although we also identify several differences between clades. As recent case studies have demonstrated, understanding both the complexity and the consistency of immune escape has important implications for CTL-based vaccine design. Phylogenetic dependency networks represent a major step toward systematically expanding our understanding of CTL escape to diverse populations and whole viral genes.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000225&type=printable |
| spellingShingle | Jonathan M Carlson Zabrina L Brumme Christine M Rousseau Chanson J Brumme Philippa Matthews Carl Kadie James I Mullins Bruce D Walker P Richard Harrigan Philip J R Goulder David Heckerman Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. PLoS Computational Biology |
| title | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. |
| title_full | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. |
| title_fullStr | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. |
| title_full_unstemmed | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. |
| title_short | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. |
| title_sort | phylogenetic dependency networks inferring patterns of ctl escape and codon covariation in hiv 1 gag |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000225&type=printable |
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