PMID- 19023406
OWN - NLM
STAT- MEDLINE
DCOM- 20090210
LR  - 20211028
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 4
IP  - 11
DP  - 2008 Nov
TI  - Phylogenetic dependency networks: inferring patterns of CTL escape and codon 
      covariation in HIV-1 Gag.
PG  - e1000225
LID - 10.1371/journal.pcbi.1000225 [doi]
LID - e1000225
AB  - 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.
FAU - Carlson, Jonathan M
AU  - Carlson JM
AD  - eScience Group, Microsoft Research, Redmond, Washington, United States of 
      America. carlson@microsoft.com
FAU - Brumme, Zabrina L
AU  - Brumme ZL
FAU - Rousseau, Christine M
AU  - Rousseau CM
FAU - Brumme, Chanson J
AU  - Brumme CJ
FAU - Matthews, Philippa
AU  - Matthews P
FAU - Kadie, Carl
AU  - Kadie C
FAU - Mullins, James I
AU  - Mullins JI
FAU - Walker, Bruce D
AU  - Walker BD
FAU - Harrigan, P Richard
AU  - Harrigan PR
FAU - Goulder, Philip J R
AU  - Goulder PJ
FAU - Heckerman, David
AU  - Heckerman D
LA  - eng
GR  - G0501777/MRC_/Medical Research Council/United Kingdom
GR  - P30 AI027757/AI/NIAID NIH HHS/United States
GR  - P30 AI060354/AI/NIAID NIH HHS/United States
GR  - R01 AI030914/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081121
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (Codon)
RN  - 0 (HIV Core Protein p24)
RN  - 0 (HLA Antigens)
RN  - 0 (Peptide Fragments)
RN  - 0 (env Gene Products, Human Immunodeficiency Virus)
RN  - 0 (p17 gag peptide, human immunodeficiency virus)
SB  - IM
MH  - Algorithms
MH  - Analysis of Variance
MH  - Codon/*genetics
MH  - Computer Simulation
MH  - Databases, Nucleic Acid
MH  - Decision Trees
MH  - Evolution, Molecular
MH  - *Genes, gag
MH  - Genetic Variation
MH  - HIV/*genetics/immunology
MH  - HIV Core Protein p24/genetics
MH  - HIV Infections/genetics/immunology/virology
MH  - HLA Antigens/*genetics/immunology
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Mutation
MH  - Peptide Fragments/genetics
MH  - Phylogeny
MH  - Selection, Genetic
MH  - T-Lymphocytes, Cytotoxic/*immunology
MH  - env Gene Products, Human Immunodeficiency Virus/genetics
PMC - PMC2579584
COIS- The authors have declared that no competing interests exist.
EDAT- 2008/11/22 09:00
MHDA- 2009/02/12 09:00
PMCR- 2008/11/21
CRDT- 2008/11/22 09:00
PHST- 2008/04/29 00:00 [received]
PHST- 2008/10/09 00:00 [accepted]
PHST- 2008/11/22 09:00 [pubmed]
PHST- 2009/02/12 09:00 [medline]
PHST- 2008/11/22 09:00 [entrez]
PHST- 2008/11/21 00:00 [pmc-release]
AID - 08-PLCB-RA-0317R2 [pii]
AID - 10.1371/journal.pcbi.1000225 [doi]
PST - ppublish
SO  - PLoS Comput Biol. 2008 Nov;4(11):e1000225. doi: 10.1371/journal.pcbi.1000225. 
      Epub 2008 Nov 21.