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The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations.

Batorsky R, Sergeev RA, Rouzine IM - PLoS Comput. Biol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Tufts University, Medford, Massachusetts, United States of America; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.

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, [Formula: see text], as well as cost to viral replication, [Formula: see text]. 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 [Formula: see text] from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss ([Formula: see text]) 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.

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Related in: MedlinePlus

Fitness loss and recognition losses of escape mutations are predicted to correlate positively, with a slope that deceases in time.Sites are randomly sampled from the simulation described in the caption to Figure 2 in order to simulate the effect of acute samples (high ranking sites), late chronic samples (low ranking sites) or patient samples from random times (random ranks). (A) No CTL decay. The slope of the correlation from acute (blue) or late chronic (red) sampled escape mutations is the same, however, it is lower for escape mutations sampled at random times (green). (B) CTL decay causes the slope of the correlation to decrease in time, due to decrease of CTL selection pressure. CTL decay is introduced as described in the caption to Figure 2 and Model.
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pcbi-1003878-g003: Fitness loss and recognition losses of escape mutations are predicted to correlate positively, with a slope that deceases in time.Sites are randomly sampled from the simulation described in the caption to Figure 2 in order to simulate the effect of acute samples (high ranking sites), late chronic samples (low ranking sites) or patient samples from random times (random ranks). (A) No CTL decay. The slope of the correlation from acute (blue) or late chronic (red) sampled escape mutations is the same, however, it is lower for escape mutations sampled at random times (green). (B) CTL decay causes the slope of the correlation to decrease in time, due to decrease of CTL selection pressure. CTL decay is introduced as described in the caption to Figure 2 and Model.

Mentions: The simulation example in Figure 2 offers an interpretation of the work by Mostowy et al [26], where a weak but statistically significant correlation was observed between fitness costs and HLA binding losses in clinically derived Pol sequences. The existence of the correlation follows from Equation 1, which states that more costly mutations will not appear unless they confer a large benefit to the virus. The model relates the weak strength of the correlation (slope  = −0.12 between the fitness decrease and the impairment of HLA binding) to the large number of active epitopes. The existence of the CTL decay caused by escape can further reduce the slope: mutations sampled during the acute phase of HIV infection are predicted to have a much larger slope than those sampled during the chronic phase (Figure 3B). Since the majority of database sequences used in the cited work fall into the latter category, the small slope of the correlation observed can partially be caused by CTL decay.


The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations.

Batorsky R, Sergeev RA, Rouzine IM - PLoS Comput. Biol. (2014)

Fitness loss and recognition losses of escape mutations are predicted to correlate positively, with a slope that deceases in time.Sites are randomly sampled from the simulation described in the caption to Figure 2 in order to simulate the effect of acute samples (high ranking sites), late chronic samples (low ranking sites) or patient samples from random times (random ranks). (A) No CTL decay. The slope of the correlation from acute (blue) or late chronic (red) sampled escape mutations is the same, however, it is lower for escape mutations sampled at random times (green). (B) CTL decay causes the slope of the correlation to decrease in time, due to decrease of CTL selection pressure. CTL decay is introduced as described in the caption to Figure 2 and Model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214571&req=5

pcbi-1003878-g003: Fitness loss and recognition losses of escape mutations are predicted to correlate positively, with a slope that deceases in time.Sites are randomly sampled from the simulation described in the caption to Figure 2 in order to simulate the effect of acute samples (high ranking sites), late chronic samples (low ranking sites) or patient samples from random times (random ranks). (A) No CTL decay. The slope of the correlation from acute (blue) or late chronic (red) sampled escape mutations is the same, however, it is lower for escape mutations sampled at random times (green). (B) CTL decay causes the slope of the correlation to decrease in time, due to decrease of CTL selection pressure. CTL decay is introduced as described in the caption to Figure 2 and Model.
Mentions: The simulation example in Figure 2 offers an interpretation of the work by Mostowy et al [26], where a weak but statistically significant correlation was observed between fitness costs and HLA binding losses in clinically derived Pol sequences. The existence of the correlation follows from Equation 1, which states that more costly mutations will not appear unless they confer a large benefit to the virus. The model relates the weak strength of the correlation (slope  = −0.12 between the fitness decrease and the impairment of HLA binding) to the large number of active epitopes. The existence of the CTL decay caused by escape can further reduce the slope: mutations sampled during the acute phase of HIV infection are predicted to have a much larger slope than those sampled during the chronic phase (Figure 3B). Since the majority of database sequences used in the cited work fall into the latter category, the small slope of the correlation observed can partially be caused by CTL decay.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Tufts University, Medford, Massachusetts, United States of America; Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America.

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, [Formula: see text], as well as cost to viral replication, [Formula: see text]. 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 [Formula: see text] from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss ([Formula: see text]) 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.

Show MeSH
Related in: MedlinePlus