Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population
Publication Date
December 22, 2015
Journal
PLOS Computational Biology
Authors
Taina T. Immonen, Jessica M. Conway, Ethan O. Romero Severson, Alan S. Perelson, et al
Volume
11
Issue
12
Pages
e1004625
DOI
https://dx.plos.org/10.1371/journal.pcbi.1004625
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1004625
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26693708
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687844
Europe PMC
http://europepmc.org/abstract/MED/26693708
Web of Science
000368521900026
Scopus
84953304347
Mendeley
http://www.mendeley.com/research/recombination-enhances-hiv1-envelope-diversity-facilitating-survival-latent-genomic-fragments-plasma
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Mendeley | Further Information

{"title"=>"Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population", "type"=>"journal", "authors"=>[{"first_name"=>"Taina T.", "last_name"=>"Immonen", "scopus_author_id"=>"36664580500"}, {"first_name"=>"Jessica M.", "last_name"=>"Conway", "scopus_author_id"=>"39660924000"}, {"first_name"=>"Ethan O.", "last_name"=>"Romero-Severson", "scopus_author_id"=>"55582068200"}, {"first_name"=>"Alan S.", "last_name"=>"Perelson", "scopus_author_id"=>"7102363214"}, {"first_name"=>"Thomas", "last_name"=>"Leitner", "scopus_author_id"=>"7004559956"}], "year"=>2015, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"15537358", "doi"=>"10.1371/journal.pcbi.1004625", "sgr"=>"84953304347", "scopus"=>"2-s2.0-84953304347", "pmid"=>"26693708", "pui"=>"607623898"}, "id"=>"e40d87ad-d31b-3239-b43b-4ff0ac90c973", "abstract"=>"HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.", "link"=>"http://www.mendeley.com/research/recombination-enhances-hiv1-envelope-diversity-facilitating-survival-latent-genomic-fragments-plasma", "reader_count"=>19, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>3, "Student > Master"=>1, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>3, "Student > Master"=>1, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>5, "Mathematics"=>2, "Agricultural and Biological Sciences"=>3, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>5}}, "reader_count_by_country"=>{"India"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2615378"], "description"=>"<p>We model interactions between and within three compartments: the latent reservoir, productively infected cells, and the immune response during generation <i>n</i>. The circles represent infected cells (both productively infected and latent), the triangles progeny virus, and the pies (circular sectors) the immune response. The colors of the circles and triangles represent different viral epitopes, and the colors in the pies indicate which viral epitopes are recognized by the immune response. Each productively infected cell produces the same number of infectious virus particles. The population of virus is sampled based on fitness to form the next set of productively infected cells, where the fitness of each virus depends on whether it is recognized by the immune response. If a new viral antigen reaches high enough numbers in the plasma, it triggers an immune response. Upon infection a small fraction of cells becomes latent. To mimic this, we assign a small probability to an infected cell moving to the latent reservoir. Also, cells in the latent reservoir have some probability of being activated and joining the replicating population. The viral sequences in productively infected cells are mutated, mimicking events that occur during reverse transcription, and the two parental strains in dually infected cells have some probability of recombining. Cells in the latent reservoir have some probability of dying, and homeostatically proliferate such that the size of the reservoir is maintained.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629315, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g001", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_schematic_/1629315", "title"=>"Model schematic.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615379"], "description"=>"<p>Grey lines correspond to the divergence (A) or diversity (B) of the sequences in each simulation, and white lines show mean of simulations. Black lines show real patient data. Note that divergence and diversity were calculated every 30 generations for 15,000 sequences in each of the 1000 simulations.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629316, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g002", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_divergence_and_diversity_of_simulated_sequences_capture_evolutionary_trends_in_clinical_data_/1629316", "title"=>"The divergence and diversity of simulated sequences capture evolutionary trends in clinical data.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615380"], "description"=>"<p>After approximately 2 years post-PHI, diversity grows linearly in the latent reservoir (blue solid line) while it starts to saturate in plasma (green solid line). Divergence in the latent reservoir (blue dashed line) grows at approximately the same rate as in the plasma (green dashed line) 6 years post-PHI.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629317, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_divergence_and_diversity_of_simulated_sequences_in_the_latent_reservoir_initially_increase_much_more_slowly_than_in_productively_infected_cells_/1629317", "title"=>"The divergence and diversity of simulated sequences in the latent reservoir initially increase much more slowly than in productively infected cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615381"], "description"=>"<p>We ordered the simulations based on the average proportion of phylogenetic lineages surviving between samplings, and formed three groups consisting of 50 simulations each, with low (mean 6%), intermediate (mean 32%), and high (mean 69%) survival of lineages, respectively. (A) Typical trees of each group. Branch lengths are according to the indicated scale. Color indicates sampling time. (B) Individual fitness landscapes (grey lines) and average profile (quadratic fit, turquoise lines) of each group. (C) Individual diversity curves (grey lines) and average trends (turquoise lines).</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629318, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g004", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tree_shape_and_diversity_are_influenced_by_the_fitness_landscape_/1629318", "title"=>"Tree shape and diversity are influenced by the fitness landscape.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615382"], "description"=>"<p>We ran 1000 simulations with the intermediate fitness landscape shown in the insert, and categorized the results based on the number of latent genomic fragments from different origins at 1% or greater frequency at 10 years post-PHI. (A) As the number of latent origins increases, so does mean sequence diversity. (B) As the number of latent origins increases, mean sequence divergence decreases.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629319, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g005", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survival_of_different_latent_genomic_fragments_increases_sequence_diversity_/1629319", "title"=>"Survival of different latent genomic fragments increases sequence diversity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615383"], "description"=>"<p>A) Simulations without recombination. B) Simulations with recombination. Grey lines show the proportion of virus with latent genomic fragments in the productively infected cell population of individual simulations, where the bold green line is the mean proportion and the thin green lines outline the 95% confidence envelope. Comparing panels A and B, clearly shows that recombination facilitates survival of latent forms.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629320, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g006", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_effect_of_recombination_on_survival_of_activated_latent_HIV_in_the_plasma_population_/1629320", "title"=>"The effect of recombination on survival of activated latent HIV in the plasma population.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615384"], "description"=>"<p>(A) The proportion of sequences with latent fragments declines rapidly as the number of latent fragments per sequence increases. (B) The number of latent sites in recombinants decreases as more latent fragments are introduced. (C) As more latent fragments exist in a sequence, they have different origins in time. The grey envelopes indicate 95% of simulation results, white lines indicate the mean, and the black lines the median trends.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629321, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g007", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Latent_genomic_fragment_patterns_/1629321", "title"=>"Latent genomic fragment patterns.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615385"], "description"=>"<p>The boxplots show the distributions of the mean proportion of lineages through time (averaged from 0 to 10 years post-PHI for the phylogeny generated from each simulation) when the number of latent genomic fragments from different origins increases. The survival of lineages increases almost linearly with the number of latent origins.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629322, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g008", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survival_of_lineages_through_time_increases_with_number_of_latent_origins_/1629322", "title"=>"Survival of lineages through time increases with number of latent origins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615386"], "description"=>"<p>(A) Distribution of time that cells have spent in the latent reservoir. (B) Distribution of the time that latent genomic fragments in plasma have spent in the latent reservoir.</p>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629323, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004625.g009", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_latency_periods_in_the_latent_reservoir_and_productively_infected_cells_/1629323", "title"=>"Distribution of latency periods in the latent reservoir and productively infected cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-05 14:53:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/2615387", "https://ndownloader.figshare.com/files/2615388", "https://ndownloader.figshare.com/files/2615389", "https://ndownloader.figshare.com/files/2615390", "https://ndownloader.figshare.com/files/2615391", "https://ndownloader.figshare.com/files/2615392", "https://ndownloader.figshare.com/files/2615393", "https://ndownloader.figshare.com/files/2615394", "https://ndownloader.figshare.com/files/2615395", "https://ndownloader.figshare.com/files/2615396", "https://ndownloader.figshare.com/files/2615397", "https://ndownloader.figshare.com/files/2615398"], "description"=>"<div><p>HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution <i>in vivo</i> by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.</p></div>", "links"=>[], "tags"=>["origins increases sequence diversity", "survival", "Latent Genomic Fragments", "selection pressure", "Recombination Enhances HIV", "envelope sequence data", "fitness landscapes", "simulation", "envelope genomic fragments", "genomic fragments", "sequence evolution", "Empirical sequence divergence", "Plasma Virus Population HIV", "virus", "recombination", "model"], "article_id"=>1629324, "categories"=>["Biological Sciences"], "users"=>["Taina T. Immonen", "Jessica M. Conway", "Ethan O. Romero-Severson", "Alan S. Perelson", "Thomas Leitner"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1004625.s001", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s002", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s003", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s004", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s005", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s006", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s007", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s008", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s009", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s010", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s011", "https://dx.doi.org/10.1371/journal.pcbi.1004625.s012"], "stats"=>{"downloads"=>16, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Recombination_Enhances_HIV_1_Envelope_Diversity_by_Facilitating_the_Survival_of_Latent_Genomic_Fragments_in_the_Plasma_Virus_Population_/1629324", "title"=>"Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2016-01-05 14:53:05"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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