Dataset Information

The Effect of Interference on the CD8(+) T Cell Escape Rates in HIV.

ABSTRACT: In early human immunodeficiency virus (HIV) infection, the virus population escapes from multiple CD8(+) cell responses. The later an escape mutation emerges, the slower it outgrows its competition, i.e., the escape rate is lower. This pattern could indicate that the strength of the CD8(+) cell responses is waning, or that later viral escape mutants carry a larger fitness cost. In this paper, we investigate whether the pattern of decreasing escape rates could also be caused by genetic interference among different escape strains. To this end, we developed a mathematical multi-epitope model of HIV dynamics, which incorporates stochastic effects, recombination, and mutation. We used cumulative linkage disequilibrium measures to quantify the amount of interference. We found that nearly synchronous, similarly strong immune responses in two-locus systems enhance the generation of genetic interference. This effect, combined with a scheme of densely spaced sampling times at the beginning of infection and sparse sampling times later, leads to decreasing successive escape rate estimates, even when there were no selection differences among alleles. These predictions are supported by empirical data from one HIV-infected patient. Thus, interference could explain why later escapes are slower. Considering escape mutations in isolation, neglecting their genetic linkage, conceals the underlying haplotype dynamics and can affect the estimation of the selective pressure exerted by CD8(+) cells. In systems in which multiple escape mutations appear, the occurrence of interference dynamics should be assessed by measuring the linkage between different escape mutations.

SUBMITTER: Garcia V

PROVIDER: S-EPMC4292734 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The Effect of Interference on the CD8(+) T Cell Escape Rates in HIV.

Garcia Victor V Regoes Roland Robert RR

Frontiers in immunology 20150113

In early human immunodeficiency virus (HIV) infection, the virus population escapes from multiple CD8(+) cell responses. The later an escape mutation emerges, the slower it outgrows its competition, i.e., the escape rate is lower. This pattern could indicate that the strength of the CD8(+) cell responses is waning, or that later viral escape mutants carry a larger fitness cost. In this paper, we investigate whether the pattern of decreasing escape rates could also be caused by genetic interferen ...[more]

PMID: 25628620

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Project description:During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV's genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains--an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction--could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies.

Dataset Information

The Effect of Interference on the CD8(+) T Cell Escape Rates in HIV.

Publications

The Effect of Interference on the CD8(+) T Cell Escape Rates in HIV.

Similar Datasets

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