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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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Dynamical selection pressure from CTLs causes three possible patterns of intra-epitope escape: Example for an epitope with two sites.Intra-epitope escape in one epitope with two sites is studied for the model shown in Figure 1 and Model. The sequence in which haplotypes are selected depends on the distribution of fitness and recognition losses within an epitope. The fraction of the infected cell population containing each of the four haplotypes in the escaping epitope is shown in “simple” (A), “leapfrog” (C) and “nested” pattern (E). For each pattern, the dependence of the escape rate (Equations 2–4) for each haplotype on the fraction of CTLs responding to the epitope (B, D, F). The inset shows CTL dynamics: the size of the CTL clone to escaping epitope (red) and the total CTL number (black). Parameters: (A,B) , (C,D) , (E,F)  with ,  for all panels; other parameters are given in Table 1.
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pcbi-1003878-g004: Dynamical selection pressure from CTLs causes three possible patterns of intra-epitope escape: Example for an epitope with two sites.Intra-epitope escape in one epitope with two sites is studied for the model shown in Figure 1 and Model. The sequence in which haplotypes are selected depends on the distribution of fitness and recognition losses within an epitope. The fraction of the infected cell population containing each of the four haplotypes in the escaping epitope is shown in “simple” (A), “leapfrog” (C) and “nested” pattern (E). For each pattern, the dependence of the escape rate (Equations 2–4) for each haplotype on the fraction of CTLs responding to the epitope (B, D, F). The inset shows CTL dynamics: the size of the CTL clone to escaping epitope (red) and the total CTL number (black). Parameters: (A,B) , (C,D) , (E,F) with , for all panels; other parameters are given in Table 1.

Mentions: The simple pattern of escape (Figure 4A) can occur if the second site cannot escape (, Equation 3). It can also occur if the second site is weakly advantageous, yet the double mutant (11) does not have time to grow to appreciable frequency before the transmitted haplotype (00) regains the advantage in growth rate. Observation of this pattern implies a large difference in the fitness costs and/or recognition loss magnitudes between the two sites in an epitope.


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)

Dynamical selection pressure from CTLs causes three possible patterns of intra-epitope escape: Example for an epitope with two sites.Intra-epitope escape in one epitope with two sites is studied for the model shown in Figure 1 and Model. The sequence in which haplotypes are selected depends on the distribution of fitness and recognition losses within an epitope. The fraction of the infected cell population containing each of the four haplotypes in the escaping epitope is shown in “simple” (A), “leapfrog” (C) and “nested” pattern (E). For each pattern, the dependence of the escape rate (Equations 2–4) for each haplotype on the fraction of CTLs responding to the epitope (B, D, F). The inset shows CTL dynamics: the size of the CTL clone to escaping epitope (red) and the total CTL number (black). Parameters: (A,B) , (C,D) , (E,F)  with ,  for all panels; other parameters are given in Table 1.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003878-g004: Dynamical selection pressure from CTLs causes three possible patterns of intra-epitope escape: Example for an epitope with two sites.Intra-epitope escape in one epitope with two sites is studied for the model shown in Figure 1 and Model. The sequence in which haplotypes are selected depends on the distribution of fitness and recognition losses within an epitope. The fraction of the infected cell population containing each of the four haplotypes in the escaping epitope is shown in “simple” (A), “leapfrog” (C) and “nested” pattern (E). For each pattern, the dependence of the escape rate (Equations 2–4) for each haplotype on the fraction of CTLs responding to the epitope (B, D, F). The inset shows CTL dynamics: the size of the CTL clone to escaping epitope (red) and the total CTL number (black). Parameters: (A,B) , (C,D) , (E,F) with , for all panels; other parameters are given in Table 1.
Mentions: The simple pattern of escape (Figure 4A) can occur if the second site cannot escape (, Equation 3). It can also occur if the second site is weakly advantageous, yet the double mutant (11) does not have time to grow to appreciable frequency before the transmitted haplotype (00) regains the advantage in growth rate. Observation of this pattern implies a large difference in the fitness costs and/or recognition loss magnitudes between the two sites in an epitope.

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