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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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The pattern of emergence of escape variants in a single epitope contains information about the fraction of recognition and fitness lost by single-site mutations in the epitope.Using simulation of the model (Figure 1A, Equations 6 to 8) with two sites per epitope, , the pattern of escape is calculated for a range of recognition and fitness losses. The pattern that is obtained is plotted as a function of the parameters of recognition loss at the first and second site ( and , respectively). In each panel, certain parameters are fixed in order to focus on the effect of recognition loss. Fixed parameters are: the escape rate of the first haplotype () and the number of targeted epitopes (), values which correspond to escape mutations that occur in acute infection (see Figure S3 for parameters that correspond to later in infection). Fitness costs are chosen such that the second site is less costly than the first:  equal to 3 (A) or much less costly than the first,  (B). Other parameters given in Table 1. Mostowy: 2012iv Equations S6 (red line) and S9 (blue line) determine the region where the leapfrog pattern can be observed. Regions that require  are not allowed by definition (magenta line). The shaded regions between these three lines correspond to regions of parameter space where both sites escape. The corresponding patterns are: “leapfrog” (, Figure 4C), “nested” (, Figure 4E), “nested leapfrog” (). Observation of the leapfrog pattern in an epitope tightly constrains the fraction of CTL recognition loss conferred by sites in an epitope. The inset shows the length of time during which haplotype 01 is dominant in the escaping epitope.
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pcbi-1003878-g005: The pattern of emergence of escape variants in a single epitope contains information about the fraction of recognition and fitness lost by single-site mutations in the epitope.Using simulation of the model (Figure 1A, Equations 6 to 8) with two sites per epitope, , the pattern of escape is calculated for a range of recognition and fitness losses. The pattern that is obtained is plotted as a function of the parameters of recognition loss at the first and second site ( and , respectively). In each panel, certain parameters are fixed in order to focus on the effect of recognition loss. Fixed parameters are: the escape rate of the first haplotype () and the number of targeted epitopes (), values which correspond to escape mutations that occur in acute infection (see Figure S3 for parameters that correspond to later in infection). Fitness costs are chosen such that the second site is less costly than the first: equal to 3 (A) or much less costly than the first, (B). Other parameters given in Table 1. Mostowy: 2012iv Equations S6 (red line) and S9 (blue line) determine the region where the leapfrog pattern can be observed. Regions that require are not allowed by definition (magenta line). The shaded regions between these three lines correspond to regions of parameter space where both sites escape. The corresponding patterns are: “leapfrog” (, Figure 4C), “nested” (, Figure 4E), “nested leapfrog” (). Observation of the leapfrog pattern in an epitope tightly constrains the fraction of CTL recognition loss conferred by sites in an epitope. The inset shows the length of time during which haplotype 01 is dominant in the escaping epitope.

Mentions: We use numeric computation to determine which pattern of escape is observed over a range of recognition and fitness losses at each of the two epitope sites. The number of epitopes is fixed, n, the escape rate for the first haplotype, , and the ratio of the fitness costs in the two epitope sites, , at values that are representative of acute infection (Figure 5) or chronic infection (Figure S3) (see Figure S1 for the range of escape rates observed in HIV infected patients). For large escape rates, the leapfrog pattern can be observed for large values of and a broad range of (Figure 5). Smaller values of produce smaller escape rates, and the leapfrog is observed in a narrow range of small (Figure S3). In some cases, haplotype 11 is observed as a short intermediate between haplotypes 10 and 01 (labeled “nested leapfrog” in Figure 5). The time interval during which a given haplotype dominates the population depends on parameters of loss and recognition at epitope site, and . The less costly haplotype can dominate the population for months to years (shown as in the inset of Figures AS3 and Figure 5). CTL to the escaping epitope will decay at the fastest rate when variant 11 dominates the population (inset Figure 4F).


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)

The pattern of emergence of escape variants in a single epitope contains information about the fraction of recognition and fitness lost by single-site mutations in the epitope.Using simulation of the model (Figure 1A, Equations 6 to 8) with two sites per epitope, , the pattern of escape is calculated for a range of recognition and fitness losses. The pattern that is obtained is plotted as a function of the parameters of recognition loss at the first and second site ( and , respectively). In each panel, certain parameters are fixed in order to focus on the effect of recognition loss. Fixed parameters are: the escape rate of the first haplotype () and the number of targeted epitopes (), values which correspond to escape mutations that occur in acute infection (see Figure S3 for parameters that correspond to later in infection). Fitness costs are chosen such that the second site is less costly than the first:  equal to 3 (A) or much less costly than the first,  (B). Other parameters given in Table 1. Mostowy: 2012iv Equations S6 (red line) and S9 (blue line) determine the region where the leapfrog pattern can be observed. Regions that require  are not allowed by definition (magenta line). The shaded regions between these three lines correspond to regions of parameter space where both sites escape. The corresponding patterns are: “leapfrog” (, Figure 4C), “nested” (, Figure 4E), “nested leapfrog” (). Observation of the leapfrog pattern in an epitope tightly constrains the fraction of CTL recognition loss conferred by sites in an epitope. The inset shows the length of time during which haplotype 01 is dominant in the escaping epitope.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003878-g005: The pattern of emergence of escape variants in a single epitope contains information about the fraction of recognition and fitness lost by single-site mutations in the epitope.Using simulation of the model (Figure 1A, Equations 6 to 8) with two sites per epitope, , the pattern of escape is calculated for a range of recognition and fitness losses. The pattern that is obtained is plotted as a function of the parameters of recognition loss at the first and second site ( and , respectively). In each panel, certain parameters are fixed in order to focus on the effect of recognition loss. Fixed parameters are: the escape rate of the first haplotype () and the number of targeted epitopes (), values which correspond to escape mutations that occur in acute infection (see Figure S3 for parameters that correspond to later in infection). Fitness costs are chosen such that the second site is less costly than the first: equal to 3 (A) or much less costly than the first, (B). Other parameters given in Table 1. Mostowy: 2012iv Equations S6 (red line) and S9 (blue line) determine the region where the leapfrog pattern can be observed. Regions that require are not allowed by definition (magenta line). The shaded regions between these three lines correspond to regions of parameter space where both sites escape. The corresponding patterns are: “leapfrog” (, Figure 4C), “nested” (, Figure 4E), “nested leapfrog” (). Observation of the leapfrog pattern in an epitope tightly constrains the fraction of CTL recognition loss conferred by sites in an epitope. The inset shows the length of time during which haplotype 01 is dominant in the escaping epitope.
Mentions: We use numeric computation to determine which pattern of escape is observed over a range of recognition and fitness losses at each of the two epitope sites. The number of epitopes is fixed, n, the escape rate for the first haplotype, , and the ratio of the fitness costs in the two epitope sites, , at values that are representative of acute infection (Figure 5) or chronic infection (Figure S3) (see Figure S1 for the range of escape rates observed in HIV infected patients). For large escape rates, the leapfrog pattern can be observed for large values of and a broad range of (Figure 5). Smaller values of produce smaller escape rates, and the leapfrog is observed in a narrow range of small (Figure S3). In some cases, haplotype 11 is observed as a short intermediate between haplotypes 10 and 01 (labeled “nested leapfrog” in Figure 5). The time interval during which a given haplotype dominates the population depends on parameters of loss and recognition at epitope site, and . The less costly haplotype can dominate the population for months to years (shown as in the inset of Figures AS3 and Figure 5). CTL to the escaping epitope will decay at the fastest rate when variant 11 dominates the population (inset Figure 4F).

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