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.

Author Summary

During the clinical course of HIV infection, an asymptomatic phase always precedes the acquired immunodeficiency syndrome (AIDS). The duration of this asymptomatic phase is highly variable among patients and reflects the rate at which the immune system gradually deteriorates. Although humoral and cell-mediated immune responses are mounted against HIV, continuous replication and adaptation allows the virus to escape host immune responses. To gain a better understanding of the role of viral evolution in disease progression, we developed a new computational technique that can estimate changes in the absolute rates of synonymous and nonsynonymous divergence through time from molecular sequences. Using this type of evolutionary inference, we have identified a previously unknown association between the “silent” evolutionary rate of HIV and the rate of disease progression in infected individuals. This finding demonstrates that cellular immune processes, which are already known to determine HIV pathogenesis, also determine viral replication rates and therefore impose important constraints on HIV evolution.