Abstract
Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection, causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, , as well as cost to viral replication, . The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of from published experimental studies to be in the range (0.01–0.86) and show that the assumption of complete recognition loss () leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be targeted by vaccines.
Highlights
HIV replication continues for years despite a highly active immune response
As early as a few weeks after infection is initiated, mutations appear in the viral genome that reduce the ability of cytotoxic T lymphocytes (CTL) to control virus replication
Of the many mutations in the viral genome that could potentially mediate viral escape from the Cytotoxic T lymphocytes (CTL) response, a specific subset are typically observed. This suggests that some mutations either entail too high a fitness cost for the virus, or are relatively inefficient escape mutations
Summary
HIV replication continues for years despite a highly active immune response. Escape mutations in CTL epitopes begin to be selected within a month of infection and continue to be selected throughout chronic infection, sometimes causing a decrease in the intrinsic replication rate of the virus (fitness cost) [8,9,10]. Among epitopes that do escape, the rate of escape slows dramatically over the first 100 days post infection. It remains unclear which parameters decide the timing and rate of escape in a given epitope as well as which epitopes escape and which are preserved throughout chronic infection [11,12,13]
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