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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 escape trajectory in the cost-benefit plane bends over time due to CTL decay.Fitness costs and recognition losses are randomly generated for 100 sites (10 epitopes with 10 sites per epitope) in order to study the sequence of escaped sites (black line) in the whole genome without CTL decay (A,B) or with CTL decay (C,D) for 1000 simulation runs. (A) For each site that escapes, the fractional fitness cost, , multiplied by the number of epitopes, , and fractional recognition loss,  (Equation 1 and Table 1) is shown. Colors show the predicted rank of escape mutations, from early escape mutations (blue) to late escape mutations (red). The average trajectory over all runs (black) moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. Inset: The best-fit slope for each escape rank. A positive correlation is observed between the fitness and recognition losses for all epitopes that escape at a given rank. (B) The maximum escape rate of any epitope site for all 10 epitopes for a representative simulation run. (C–D) As in (A–B), except including CTL decay. CTL decay is simulated by reducing recognition losses for all epitope sites in epitopes that have partially escaped according to , summing over all i sites in the epitope that have escaped with  per escape. When CTLs decay in response to an escape in an epitope, the immune pressure on all other sites in that epitope is decreased. The result is that the average trajectory in the cost-benefit plane bends towards the horizontal axis.
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pcbi-1003878-g002: The escape trajectory in the cost-benefit plane bends over time due to CTL decay.Fitness costs and recognition losses are randomly generated for 100 sites (10 epitopes with 10 sites per epitope) in order to study the sequence of escaped sites (black line) in the whole genome without CTL decay (A,B) or with CTL decay (C,D) for 1000 simulation runs. (A) For each site that escapes, the fractional fitness cost, , multiplied by the number of epitopes, , and fractional recognition loss, (Equation 1 and Table 1) is shown. Colors show the predicted rank of escape mutations, from early escape mutations (blue) to late escape mutations (red). The average trajectory over all runs (black) moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. Inset: The best-fit slope for each escape rank. A positive correlation is observed between the fitness and recognition losses for all epitopes that escape at a given rank. (B) The maximum escape rate of any epitope site for all 10 epitopes for a representative simulation run. (C–D) As in (A–B), except including CTL decay. CTL decay is simulated by reducing recognition losses for all epitope sites in epitopes that have partially escaped according to , summing over all i sites in the epitope that have escaped with per escape. When CTLs decay in response to an escape in an epitope, the immune pressure on all other sites in that epitope is decreased. The result is that the average trajectory in the cost-benefit plane bends towards the horizontal axis.

Mentions: The process of gradual viral escape from the immune response of an infected host continues for years. During this time, the virus shows a limited number of detectable CTL responses against different sites ([33]) where a total of 5–30 escape mutations are selected [11], [30]. We investigate the trajectory connecting these escape mutations in the cost-benefit plane and predict how the average fitness costs and recognition losses incurred by an escape mutation will change as escape progresses. For this aim, we use a simplified version of the main model (see Materials and Methods), focused only on the order of escape mutations (i.e., model dynamics are not considered explicitly). Parameters and are randomly generated for a genome with multiple epitopes and multiple sites per epitope (10 epitopes, with 10 sites per epitope in Figure 2) and epitope sites are ranked in the descending order of escape rate (Equation 1). When many random runs are compared, a correlation between and for escape mutations of a given rank is observed (Figure 2A). The average trajectory of escape in the cost-benefit plane moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. The maximum escape rate per epitope decreases over many rounds of escape (Figure 2B) and each epitope escapes at more than one site. This prediction is consistent with experimental observation, where the majority of escaping epitopes undergo more than one mutation [13], [30].


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 escape trajectory in the cost-benefit plane bends over time due to CTL decay.Fitness costs and recognition losses are randomly generated for 100 sites (10 epitopes with 10 sites per epitope) in order to study the sequence of escaped sites (black line) in the whole genome without CTL decay (A,B) or with CTL decay (C,D) for 1000 simulation runs. (A) For each site that escapes, the fractional fitness cost, , multiplied by the number of epitopes, , and fractional recognition loss,  (Equation 1 and Table 1) is shown. Colors show the predicted rank of escape mutations, from early escape mutations (blue) to late escape mutations (red). The average trajectory over all runs (black) moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. Inset: The best-fit slope for each escape rank. A positive correlation is observed between the fitness and recognition losses for all epitopes that escape at a given rank. (B) The maximum escape rate of any epitope site for all 10 epitopes for a representative simulation run. (C–D) As in (A–B), except including CTL decay. CTL decay is simulated by reducing recognition losses for all epitope sites in epitopes that have partially escaped according to , summing over all i sites in the epitope that have escaped with  per escape. When CTLs decay in response to an escape in an epitope, the immune pressure on all other sites in that epitope is decreased. The result is that the average trajectory in the cost-benefit plane bends towards the horizontal axis.
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Related In: Results  -  Collection

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

pcbi-1003878-g002: The escape trajectory in the cost-benefit plane bends over time due to CTL decay.Fitness costs and recognition losses are randomly generated for 100 sites (10 epitopes with 10 sites per epitope) in order to study the sequence of escaped sites (black line) in the whole genome without CTL decay (A,B) or with CTL decay (C,D) for 1000 simulation runs. (A) For each site that escapes, the fractional fitness cost, , multiplied by the number of epitopes, , and fractional recognition loss, (Equation 1 and Table 1) is shown. Colors show the predicted rank of escape mutations, from early escape mutations (blue) to late escape mutations (red). The average trajectory over all runs (black) moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. Inset: The best-fit slope for each escape rank. A positive correlation is observed between the fitness and recognition losses for all epitopes that escape at a given rank. (B) The maximum escape rate of any epitope site for all 10 epitopes for a representative simulation run. (C–D) As in (A–B), except including CTL decay. CTL decay is simulated by reducing recognition losses for all epitope sites in epitopes that have partially escaped according to , summing over all i sites in the epitope that have escaped with per escape. When CTLs decay in response to an escape in an epitope, the immune pressure on all other sites in that epitope is decreased. The result is that the average trajectory in the cost-benefit plane bends towards the horizontal axis.
Mentions: The process of gradual viral escape from the immune response of an infected host continues for years. During this time, the virus shows a limited number of detectable CTL responses against different sites ([33]) where a total of 5–30 escape mutations are selected [11], [30]. We investigate the trajectory connecting these escape mutations in the cost-benefit plane and predict how the average fitness costs and recognition losses incurred by an escape mutation will change as escape progresses. For this aim, we use a simplified version of the main model (see Materials and Methods), focused only on the order of escape mutations (i.e., model dynamics are not considered explicitly). Parameters and are randomly generated for a genome with multiple epitopes and multiple sites per epitope (10 epitopes, with 10 sites per epitope in Figure 2) and epitope sites are ranked in the descending order of escape rate (Equation 1). When many random runs are compared, a correlation between and for escape mutations of a given rank is observed (Figure 2A). The average trajectory of escape in the cost-benefit plane moves from high recognition loss, low fitness cost to low recognition loss, high fitness cost. The maximum escape rate per epitope decreases over many rounds of escape (Figure 2B) and each epitope escapes at more than one site. This prediction is consistent with experimental observation, where the majority of escaping epitopes undergo more than one mutation [13], [30].

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