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.
Highlights
The clinical course of HIV infection is generally well-defined, there is considerable variability among patients in rates of disease progression
Cytotoxic time since seroconversion (Ts) cell (CTL) responses play a more important protective role in HIV infection, and evidence has shown that partial control of HIV replication in vivo is temporally associated with the appearance of cytotoxic T cell (CTL) responses [4] and that the rate of disease progression is strongly dependent on human leukocyte antigen (HLA) class I alleles [5,6]
Humoral and cell-mediated immune responses are mounted against HIV, continuous replication and adaptation allows the virus to escape host immune responses
Summary
The clinical course of HIV infection is generally well-defined, there is considerable variability among patients in rates of disease progression. The highly variable asymptomatic phase, ranging from several months to more than 20 years, most likely reflects differences in the nature of the evolutionary arms race between the virus population and the host immune system. Both humoral and cell-mediated immune responses are mounted against the virus but are eventually defeated by HIV replication and adaptation. As part of this process, neutralizing antibodies (nAbs) exert a strong selective pressure on the HIV envelope gene (env) [1,2] but do not control viral replication, and nAb levels are not predictive of disease progression [3]. CTLs may not be responsible for the majority of infected cell deaths, small differences in CTL killing rates could still be clinically relevant and alter the time of disease onset [7]
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