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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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A computational model of the interaction between HIV and multiple CTL clones.(A) The model given by Equations 6 to 8 comprises three interacting cell compartments: target cells (T), infected cells (I) and multiple CTL clones (E). Viral genomes contain multiple epitopes, which can mutate to partially abrogate CTL recognition. An escape mutation is denoted by an X. Each CTL clone recognizes a single viral epitope and is stimulated to divide at a rate proportional to the number of infected cells with recognizable epitopes. The model is designed to study the rate of escape in epitopes when CTL pressure is distributed across multiple epitopes, as well as study intra-epitope escape patterns when CTL respond dynamically to the infected cells that they recognize. Black arrows: flux of cells from one compartment to another. Blue arrows: dependence of the rate of flux from one compartment on another. Dotted lines represent attenuation of the interaction strength. (B) Simulation example showing three phases of HIV evolution. A single virus strain initiates the infection (transmitted strain, black). In response to the growing number of infected cells, multiple CTL clones are activated (colored lines), and the system reaches a steady state. Finally, virus strains with escape mutations (dashed, colored lines) replace the transmitted strain. In response to lowered activation signals, some CTL clones decline. The escape strains are colored to match the CTL against which an escape was most recently acquired. Model parameters: number of epitopes, ; number of sites per epitope, . Epitopes 1–3 have parameters that allow escape , epitopes 4–6 have parameters that prohibit escape, . Other parameters are listed in Table 1.
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pcbi-1003878-g001: A computational model of the interaction between HIV and multiple CTL clones.(A) The model given by Equations 6 to 8 comprises three interacting cell compartments: target cells (T), infected cells (I) and multiple CTL clones (E). Viral genomes contain multiple epitopes, which can mutate to partially abrogate CTL recognition. An escape mutation is denoted by an X. Each CTL clone recognizes a single viral epitope and is stimulated to divide at a rate proportional to the number of infected cells with recognizable epitopes. The model is designed to study the rate of escape in epitopes when CTL pressure is distributed across multiple epitopes, as well as study intra-epitope escape patterns when CTL respond dynamically to the infected cells that they recognize. Black arrows: flux of cells from one compartment to another. Blue arrows: dependence of the rate of flux from one compartment on another. Dotted lines represent attenuation of the interaction strength. (B) Simulation example showing three phases of HIV evolution. A single virus strain initiates the infection (transmitted strain, black). In response to the growing number of infected cells, multiple CTL clones are activated (colored lines), and the system reaches a steady state. Finally, virus strains with escape mutations (dashed, colored lines) replace the transmitted strain. In response to lowered activation signals, some CTL clones decline. The escape strains are colored to match the CTL against which an escape was most recently acquired. Model parameters: number of epitopes, ; number of sites per epitope, . Epitopes 1–3 have parameters that allow escape , epitopes 4–6 have parameters that prohibit escape, . Other parameters are listed in Table 1.

Mentions: In order to study escape from the immune response we consider a model that includes target cells, infected cells and multiple CTL clones which recognize regions in the viral genome (epitopes) with equal avidities (Figure 1A and Materials and Methods). The model predicts three distinct phases of HIV infection (Figure 1B), as follows. Phase 1: The transmitted HIV strain expands in the population of target cells. Phase 2: All CTL clones that recognize cells infected by the transmitted strain are activated, expand, and reduce the number of infected cells. A steady state is obtained with constant levels of infected cells and CTL, which represents chronic HIV infection (see Equations S1–S3). Phase 3: Escape mutations in viral epitopes emerge, changing the genetic composition of the population of infected cells and the clonal composition of the CTL population but only weakly affecting their overall sizes.


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)

A computational model of the interaction between HIV and multiple CTL clones.(A) The model given by Equations 6 to 8 comprises three interacting cell compartments: target cells (T), infected cells (I) and multiple CTL clones (E). Viral genomes contain multiple epitopes, which can mutate to partially abrogate CTL recognition. An escape mutation is denoted by an X. Each CTL clone recognizes a single viral epitope and is stimulated to divide at a rate proportional to the number of infected cells with recognizable epitopes. The model is designed to study the rate of escape in epitopes when CTL pressure is distributed across multiple epitopes, as well as study intra-epitope escape patterns when CTL respond dynamically to the infected cells that they recognize. Black arrows: flux of cells from one compartment to another. Blue arrows: dependence of the rate of flux from one compartment on another. Dotted lines represent attenuation of the interaction strength. (B) Simulation example showing three phases of HIV evolution. A single virus strain initiates the infection (transmitted strain, black). In response to the growing number of infected cells, multiple CTL clones are activated (colored lines), and the system reaches a steady state. Finally, virus strains with escape mutations (dashed, colored lines) replace the transmitted strain. In response to lowered activation signals, some CTL clones decline. The escape strains are colored to match the CTL against which an escape was most recently acquired. Model parameters: number of epitopes, ; number of sites per epitope, . Epitopes 1–3 have parameters that allow escape , epitopes 4–6 have parameters that prohibit escape, . Other parameters are listed in Table 1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4214571&req=5

pcbi-1003878-g001: A computational model of the interaction between HIV and multiple CTL clones.(A) The model given by Equations 6 to 8 comprises three interacting cell compartments: target cells (T), infected cells (I) and multiple CTL clones (E). Viral genomes contain multiple epitopes, which can mutate to partially abrogate CTL recognition. An escape mutation is denoted by an X. Each CTL clone recognizes a single viral epitope and is stimulated to divide at a rate proportional to the number of infected cells with recognizable epitopes. The model is designed to study the rate of escape in epitopes when CTL pressure is distributed across multiple epitopes, as well as study intra-epitope escape patterns when CTL respond dynamically to the infected cells that they recognize. Black arrows: flux of cells from one compartment to another. Blue arrows: dependence of the rate of flux from one compartment on another. Dotted lines represent attenuation of the interaction strength. (B) Simulation example showing three phases of HIV evolution. A single virus strain initiates the infection (transmitted strain, black). In response to the growing number of infected cells, multiple CTL clones are activated (colored lines), and the system reaches a steady state. Finally, virus strains with escape mutations (dashed, colored lines) replace the transmitted strain. In response to lowered activation signals, some CTL clones decline. The escape strains are colored to match the CTL against which an escape was most recently acquired. Model parameters: number of epitopes, ; number of sites per epitope, . Epitopes 1–3 have parameters that allow escape , epitopes 4–6 have parameters that prohibit escape, . Other parameters are listed in Table 1.
Mentions: In order to study escape from the immune response we consider a model that includes target cells, infected cells and multiple CTL clones which recognize regions in the viral genome (epitopes) with equal avidities (Figure 1A and Materials and Methods). The model predicts three distinct phases of HIV infection (Figure 1B), as follows. Phase 1: The transmitted HIV strain expands in the population of target cells. Phase 2: All CTL clones that recognize cells infected by the transmitted strain are activated, expand, and reduce the number of infected cells. A steady state is obtained with constant levels of infected cells and CTL, which represents chronic HIV infection (see Equations S1–S3). Phase 3: Escape mutations in viral epitopes emerge, changing the genetic composition of the population of infected cells and the clonal composition of the CTL population but only weakly affecting their overall sizes.

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