1. Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection
- Author
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Victor, Garcia, Marcus W, Feldman, and Roland R, Regoes
- Subjects
RNA viruses ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Pathology and Laboratory Medicine ,Computational biology ,Immunodeficiency Viruses ,Cellular types ,Medicine and Health Sciences ,lcsh:QH301-705.5 ,Genetic Interference ,Immune evasion ,Immune cells ,Medical Microbiology ,Viral Pathogens ,Viruses ,White blood cells ,Infectious diseases ,Pathogens ,Research Article ,HIV infections ,Cell biology ,Blood cells ,Population Size ,Immunology ,T cells ,Cytotoxic T cells ,Viral diseases ,Microbiology ,Evolution, Molecular ,Population Metrics ,571: Physiologie und verwandte Themen ,Retroviruses ,Genetics ,Point Mutation ,Humans ,Microbial Pathogens ,Evolutionary Biology ,Population Biology ,CD8+ T-Lymphocytes ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Animal cells ,Haplotypes ,lcsh:Biology (General) ,Mutation ,HIV-1 ,Molecular evolution ,Population Genetics - Abstract
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., Author Summary Within-host evolution of human immunodeficiency virus (HIV) is shaped by strong immune responses mounted against the virus. Multiple CD8+ T cell populations, each recognizing a specific part of an HIV protein, simultaneously suppress HIV growth. Escape mutations that arise in HIV genome regions coding for these virion protein parts, impair CD8+ T cell recognition and are consequently strongly selected. The emergence and rise of these escape mutations exhibits an intriguing temporal pattern: the earlier an escape mutation arises, the faster it goes to fixation. This pattern is termed escape rate decrease (ERD). In this paper, we tested computationally whether interference, i.e. the coexistence of multiple genetically distinct HIV strains engaged in competitive interaction within the host, could be a possible source of ERD. As an alternative, we also mathematically derived the temporal pattern of escapes under interference-free conditions, and compared this with data. We found that interference between multiple beneficial mutations could generate ERD. However, ERD does not imply the presence of interference. Thus, more detailed data is required to unambiguously determine whether interference effects influence ERD generation. Nevertheless, interference should be considered when studying the within-host evolution of HIV. Ignoring its effects on population dynamics can severely underestimate the protective capacity of CD8+ T cells.
- Published
- 2016
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