Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 3, Issue 2, Pages 282-292Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.0030029
Keywords
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Funding
- NIAID NIH HHS [AI47745, U01 AI043638, AI43638, AI36214, R21 AI047745, R56 AI047745, R01 AI047745, AI57167, P30 AI036214, R01 AI057167] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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.
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