title: Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics.
abstract: Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new "relaxed-clock" phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse.
authors.affiliation: Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.forename: Sergei L
authors.initials: SL
authors.lastname: Kosakovsky Pond
authors.forename: Alexei J
authors.initials: AJ
authors.lastname: Drummond
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Pybus
authors.forename: Beth
authors.initials: B
authors.lastname: Shapiro
authors.forename: Helena
authors.initials: H
authors.lastname: Barroso
authors.forename: Nuno
authors.initials: N
authors.lastname: Taveira
authors.forename: Andrew
authors.initials: A
authors.lastname: Rambaut
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D003062:Codon / Q000235:genetics; D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D015658:HIV Infections / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D014759:Viral Envelope Proteins / Q000235:genetics*; D014775:Virus Activation / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*
chemical_list: D003062:Codon; D014759:Viral Envelope Proteins