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Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression.

Lee HY, Perelson AS, Park SC, Leitner T - PLoS Comput. Biol. (2008)

Bottom Line: We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants.The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces.In agreement with our modeling, in 13 out of 15 patients (followed for 3-12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, NY, USA. hayoun@bst.rochester.edu

ABSTRACT
Quantifying the dynamics of intrahost HIV-1 sequence evolution is one means of uncovering information about the interaction between HIV-1 and the host immune system. In the chronic phase of infection, common dynamics of sequence divergence and diversity have been reported. We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants. The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces. Analysis of the model suggested that the previously observed saturation of divergence and decrease of diversity in later stages of infection can be explained by a decrease in the proportion of offspring that are mutants as the distance from the founder strain increases rather than due to an increase of viral fitness. The prediction of the model was examined by performing phylogenetic analysis to estimate the change in the rate of evolution during infection. In agreement with our modeling, in 13 out of 15 patients (followed for 3-12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline. The correlation between the dynamics of the evolutionary rate and the rate of CD4+ T-cell decline, coupled with our HIV-1 sequence evolution model, explains previously conflicting observations of the relationships between the rate of HIV-1 quasispecies evolution and disease progression.

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Dynamics of divergence and diversity with fitness reduction.Dynamics of divergence and diversity when fitness is reduced to                                50% of its original value for                                        d>dc = 50                                mutations. For d≤50,                                f = 1 and for                                    d>50,                                f = 0.5, and                                    M(d) = 0.5                                for all d. The saturation of divergence and the                                decrease of diversity are observed.
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pcbi-1000240-g005: Dynamics of divergence and diversity with fitness reduction.Dynamics of divergence and diversity when fitness is reduced to 50% of its original value for d>dc = 50 mutations. For d≤50, f = 1 and for d>50, f = 0.5, and M(d) = 0.5 for all d. The saturation of divergence and the decrease of diversity are observed.

Mentions: Second, we studied the case where the fitness is reduced after a given distance, F(d) = f for d≤dc and F(d) = f′ for d>dc where f′ is less than f. Here the proportion of offsprings that are mutants is constant for all viruses, M(d) = 0.5. We found that reduced fitness for viruses with a distance greater than dc reproduced the observed patterns for divergence and diversity. Figure 5 displays the calculated dynamics of divergence and diversity when we reduce the fitness of viruses having a distance greater than 50 mutations to 50% of the fitness of viruses with a distance less than 50 mutations. Although the profile of reduced fitness for the viruses after a given distance qualitatively explain the common dynamics of divergence and diversity, the reduction in the fitness of a virus population at later stages does not seem realistic considering the observation of increased fitness over the course of infection [6].


Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression.

Lee HY, Perelson AS, Park SC, Leitner T - PLoS Comput. Biol. (2008)

Dynamics of divergence and diversity with fitness reduction.Dynamics of divergence and diversity when fitness is reduced to                                50% of its original value for                                        d>dc = 50                                mutations. For d≤50,                                f = 1 and for                                    d>50,                                f = 0.5, and                                    M(d) = 0.5                                for all d. The saturation of divergence and the                                decrease of diversity are observed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2602878&req=5

pcbi-1000240-g005: Dynamics of divergence and diversity with fitness reduction.Dynamics of divergence and diversity when fitness is reduced to 50% of its original value for d>dc = 50 mutations. For d≤50, f = 1 and for d>50, f = 0.5, and M(d) = 0.5 for all d. The saturation of divergence and the decrease of diversity are observed.
Mentions: Second, we studied the case where the fitness is reduced after a given distance, F(d) = f for d≤dc and F(d) = f′ for d>dc where f′ is less than f. Here the proportion of offsprings that are mutants is constant for all viruses, M(d) = 0.5. We found that reduced fitness for viruses with a distance greater than dc reproduced the observed patterns for divergence and diversity. Figure 5 displays the calculated dynamics of divergence and diversity when we reduce the fitness of viruses having a distance greater than 50 mutations to 50% of the fitness of viruses with a distance less than 50 mutations. Although the profile of reduced fitness for the viruses after a given distance qualitatively explain the common dynamics of divergence and diversity, the reduction in the fitness of a virus population at later stages does not seem realistic considering the observation of increased fitness over the course of infection [6].

Bottom Line: We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants.The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces.In agreement with our modeling, in 13 out of 15 patients (followed for 3-12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, NY, USA. hayoun@bst.rochester.edu

ABSTRACT
Quantifying the dynamics of intrahost HIV-1 sequence evolution is one means of uncovering information about the interaction between HIV-1 and the host immune system. In the chronic phase of infection, common dynamics of sequence divergence and diversity have been reported. We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants. The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces. Analysis of the model suggested that the previously observed saturation of divergence and decrease of diversity in later stages of infection can be explained by a decrease in the proportion of offspring that are mutants as the distance from the founder strain increases rather than due to an increase of viral fitness. The prediction of the model was examined by performing phylogenetic analysis to estimate the change in the rate of evolution during infection. In agreement with our modeling, in 13 out of 15 patients (followed for 3-12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline. The correlation between the dynamics of the evolutionary rate and the rate of CD4+ T-cell decline, coupled with our HIV-1 sequence evolution model, explains previously conflicting observations of the relationships between the rate of HIV-1 quasispecies evolution and disease progression.

Show MeSH
Related in: MedlinePlus