title: Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag.
abstract: 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.
authors.affiliation: eScience Group, Microsoft Research, Redmond, Washington, United States of America. carlson@microsoft.com
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Christine M
authors.initials: CM
authors.lastname: Rousseau
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Philippa
authors.initials: P
authors.lastname: Matthews
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
mesh_terms: D000465:Algorithms; D000704:Analysis of Variance; D003062:Codon / Q000235:genetics*; D003198:Computer Simulation; D030561:Databases, Nucleic Acid; D003663:Decision Trees; D019143:Evolution, Molecular; D015750:Genes, gag; D014644:Genetic Variation; D006678:HIV / Q000235:genetics* / Q000276:immunology; D016655:HIV Core Protein p24 / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics; D010802:Phylogeny; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D003062:Codon; D016655:HIV Core Protein p24; D006680:HLA Antigens; D010446:Peptide Fragments; D054299:env Gene Products, Human Immunodeficiency Virus; C473991:p17 gag peptide, human immunodeficiency virus