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Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics

Lemey, P
; 
Kosakovsky Pond, SL
; 
Drummond, AJ
; 
Pybus, OG
; 
Shapiro, B
; 
Barroso, H
; 
Taveira, N
; 
Rambaut, A
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Journal Article
Date
2007-01-01
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Department
Subject
Amino Acid Sequence
 Amino Acid Substitution
 Codon
 Computer Simulation
 DNA Mutational Analysis
 Disease Progression
 Evolution, Molecular
 Genetic Predisposition to Disease
 Genetic Variation
 HIV Infections
 Humans
 Models, Genetic
 Molecular Sequence Data
 Viral Envelope Proteins
 Virus Activation
 Virus Replication
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http://hdl.handle.net/20.500.12613/5626
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10.1371/journal.pcbi.0030029
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. © 2007 Lemey et al.
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PLoS Computational Biology
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