HIV-1 Env C2-V4 Diversification in a Slow-Progressor Infant Reveals a Flat but Rugged Fitness Landscape
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{"title"=>"HIV-1 Env C2-V4 Diversification in a Slow-Progressor Infant Reveals a Flat but Rugged Fitness Landscape", "type"=>"journal", "authors"=>[{"first_name"=>"S. Abigail", "last_name"=>"Smith", "scopus_author_id"=>"25825714700"}, {"first_name"=>"Charles", "last_name"=>"Wood", "scopus_author_id"=>"35313158100"}, {"first_name"=>"John T.", "last_name"=>"West", "scopus_author_id"=>"7402746910"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"368833115", "issn"=>"19326203", "pmid"=>"23638182", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0063094", "sgr"=>"84876943804", "scopus"=>"2-s2.0-84876943804"}, "id"=>"da263c74-1431-3883-9c90-71c0c214f7c3", "abstract"=>"Human immunodeficiency virus type-1 (HIV-1) fitness has been associated with virus entry, a process mediated by the envelope glycoprotein (Env). We previously described Env genetic diversification in a Zambian, subtype C infected, slow-progressor child (1157i) in parallel with an evolving neutralizing antibody response. Because of the role the Variable-3 loop (V3) plays in transmission, cell tropism, neutralization sensitivity, and fitness, longitudinally isolated 1157i C2-V4 alleles were cloned into HIV-1NL4-3-eGFP and -DsRed2 infectious molecular clones. The fluorescent reporters allowed for dual-infection competitions between all patient-derived C2-V4 chimeras to quantify the effect of V3 diversification and selection on fitness. 'Winners' and 'losers' were readily discriminated among the C2-V4 alleles. Exceptional sensitivity for detection of subtle fitness differences was revealed through analysis of two alleles differing in a single synonymous amino acid. However, when the outcomes of N = 33 competitions were averaged for each chimera, the aggregate analysis showed that despite increasing diversification and divergence with time, natural selection of C2-V4 sequences in this individual did not appear to be producing a 'survival of the fittest' evolutionary pattern. Rather, we detected a relatively flat fitness landscape consistent with mutational robustness. Fitness outcomes were then correlated with individual components of the entry process. Env incorporation into particles correlated best with fitness, suggesting a role for Env avidity, as opposed to receptor/coreceptor affinity, in defining fitness. Nevertheless, biochemical analyses did not identify any step in HIV-1 entry as a dominant determinant of fitness. Our results lead us to conclude that multiple aspects of entry contribute to maintaining adequate HIV-1 fitness, and there is no surrogate analysis for determining fitness. The capacity for subtle polymorphisms in Env to nevertheless significantly impact viral fitness suggests fitness is best defined by head-to-head competition.", "link"=>"http://www.mendeley.com/research/hiv1-env-c2v4-diversification-slowprogressor-infant-reveals-flat-rugged-fitness-landscape", "reader_count"=>9, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>3, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1048188"], "description"=>"<p>Each C2-V4 patient chimera (DsRed2) was competed against all others (eGFP) in triplicate. W<sub>RED</sub> was calculated for each competition, and plotted in aggregate for each chimera. Black bars represent mean, and 95% CI.</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "chimera"], "article_id"=>693672, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g005", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Aggregate_data_from_all_patient_chimera_competitions_/693672", "title"=>"Aggregate data from all patient chimera competitions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048186"], "description"=>"<p><b>a)</b> U87.CD4.CCR5 cells were infected with NL4-3-67m15-eGFP, NL4-3-67m15-DsRED2 at a MOI of 0.1 in mono- and dual-infections. The numbers of fluorescent events were enumerated by flow cytometry. The numbers of events were then used to calculate relative fitness (W) values. This process was carried out for all competitions, in triplicate. <b>b)</b> The resulting W values from all NL4-3-00m06-DsRED2 vs. all other viruses in eGFP, and <b>c)</b> NL4-3-00m15-DsRED2 vs. all other viruses in eGFP. Circles represent individual W values, black bars represent means, and error bars represent standard deviation. Results from all chimeras in <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063094#pone.0063094.s004\" target=\"_blank\">Fig. S4</a></b>.</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "chimera"], "article_id"=>693670, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Results_from_individual_patient_chimera_competitions_/693670", "title"=>"Results from individual patient chimera competitions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048183"], "description"=>"<p><b>a)</b> U87.CD4.CXCR4 cells were infected at a MOI of 0.1 with NL4-3-MSS-eGFP, NL4-3-MSS-DsRED2, or both viral variants. Five days post-infection, cells were imaged by fluorescent microscopy (40×). <b>b)</b> Fluorescent events from mono- and dual-infection of U87.CD4.CXCR4 cells at MOI of 0.1 and 0.01 were enumerated by flow cytometry. Fluorescent cells were quantified on an Influx cell sorter, excitation 488-nm (eGFP) and 561-nm (DsRed2). MOI of 1.0 was not quantified due cell death in mono- and dual-infections, as well as the presence of dually infected cells (double positive ‘yellow’ cells).</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "molecular", "clones", "fluorescent"], "article_id"=>693667, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Infectious_molecular_clones_express_fluorescent_protein_reporter_upon_infection_of_target_cells_/693667", "title"=>"Infectious molecular clones express fluorescent protein reporter upon infection of target cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048196"], "description"=>"<p><b>a)</b> Infectivity of each chimera was assayed via luciferase activity of TZM-bl cells (Relative Light Units, RLU), relative to p66, as determined by immunoprecipitation of radiolabeled virions (see <b>Fig. 5c</b>), relative to wild-type NL4-3, in triplicate. <b>b)</b> The average infectivity value was plotted against average relative fitness values, and revealed a modest correlation (R<sup>2</sup> = 0.4448) (dashed lines 95% CI). <b>c)</b> The ratio of average infectivity to average incorporation of Env was calculated to determine average infectivity per incorporated Env. <b>d)</b> When this ratio was plotted verses average relative fitness values, there was no correlation (R<sup>2</sup> = 0.1058) (dashed lines 95% CI).</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "infectivity", "incorporated", "env"], "article_id"=>693680, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g007", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chimera_infectivity_has_a_modest_correlation_with_fitness_while_infectivity_per_incorporated_Env_does_not_/693680", "title"=>"Chimera infectivity has a modest correlation with fitness, while infectivity per incorporated Env does not.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048194"], "description"=>"<p><b>a)</b> 293T cells were transfected with patient eGFP chimeras. 24-hours post-transfection, cells were radiolabeled with <sup>35</sup>S. Cells were lysed at the indicated time-points, immunoprecipitated with HIV-Ig, and resolved by SDS-PAGE in order to quantify the processing of gp160 and accumulation of gp120. To quantify the processing of Env, the slope of the ratio of gp120 to gp160 verses time was calculated for each chimera (00m06, 00m15, 12m04 shown). <b>b)</b> Slope values were plotted against average relative fitness values to determine correlation (dashed lines 95% CI). <b>c)</b> Supernatants from radiolabeled 293T patient eGFP chimeras’ transfections were pelleted, lysed, and immunoprecipitated with HIV-Ig. SDS-PAGE was used to resolve gp120 and p66 protein bands for calculating incorporation of Env relative to wild-type virus, in triplicate. <b>d)</b> This ratio was plotted against relative fitness values, and revealed a modest positive correlation (R<sup>2</sup> = 0.4349) (dashed lines 95% CI).</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "chimeras", "env"], "article_id"=>693678, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g006", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Patient_chimeras_differ_in_Env_processing_and_incorporation_/693678", "title"=>"Patient chimeras differ in Env processing and incorporation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048202", "https://ndownloader.figshare.com/files/1048203", "https://ndownloader.figshare.com/files/1048204", "https://ndownloader.figshare.com/files/1048206", "https://ndownloader.figshare.com/files/1048207", "https://ndownloader.figshare.com/files/1048209", "https://ndownloader.figshare.com/files/1048210", "https://ndownloader.figshare.com/files/1048211"], "description"=>"<div><p>Human immunodeficiency virus type-1 (HIV-1) fitness has been associated with virus entry, a process mediated by the envelope glycoprotein (Env). We previously described Env genetic diversification in a Zambian, subtype C infected, slow-progressor child (1157i) in parallel with an evolving neutralizing antibody response. Because of the role the Variable-3 loop (V3) plays in transmission, cell tropism, neutralization sensitivity, and fitness, longitudinally isolated 1157i C2-V4 alleles were cloned into HIV-1<sub>NL4-3</sub>-eGFP and -DsRed2 infectious molecular clones. The fluorescent reporters allowed for dual-infection competitions between all patient-derived C2-V4 chimeras to quantify the effect of V3 diversification and selection on fitness. ‘Winners’ and ‘losers’ were readily discriminated among the C2-V4 alleles. Exceptional sensitivity for detection of subtle fitness differences was revealed through analysis of two alleles differing in a single synonymous amino acid. However, when the outcomes of N = 33 competitions were averaged for each chimera, the aggregate analysis showed that despite increasing diversification and divergence with time, natural selection of C2-V4 sequences in this individual did not appear to be producing a ‘survival of the fittest’ evolutionary pattern. Rather, we detected a relatively flat fitness landscape consistent with mutational robustness. Fitness outcomes were then correlated with individual components of the entry process. Env incorporation into particles correlated best with fitness, suggesting a role for Env avidity, as opposed to receptor/coreceptor affinity, in defining fitness. Nevertheless, biochemical analyses did not identify any step in HIV-1 entry as a dominant determinant of fitness. Our results lead us to conclude that multiple aspects of entry contribute to maintaining adequate HIV-1 fitness, and there is no surrogate analysis for determining fitness. The capacity for subtle polymorphisms in Env to nevertheless significantly impact viral fitness suggests fitness is best defined by head-to-head competition.</p> </div>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "env", "c2-v4", "diversification", "slow-progressor", "reveals", "rugged"], "article_id"=>693686, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0063094.s001", "https://dx.doi.org/10.1371/journal.pone.0063094.s002", "https://dx.doi.org/10.1371/journal.pone.0063094.s003", "https://dx.doi.org/10.1371/journal.pone.0063094.s004", "https://dx.doi.org/10.1371/journal.pone.0063094.s005", "https://dx.doi.org/10.1371/journal.pone.0063094.s006", "https://dx.doi.org/10.1371/journal.pone.0063094.s007", "https://dx.doi.org/10.1371/journal.pone.0063094.s008"], "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIV_1_Env_C2_V4_Diversification_in_a_Slow_Progressor_Infant_Reveals_a_Flat_but_Rugged_Fitness_Landscape_/693686", "title"=>"HIV-1 Env C2-V4 Diversification in a Slow-Progressor Infant Reveals a Flat but Rugged Fitness Landscape", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-04-29 01:01:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048184"], "description"=>"<p><b>a)</b> Stimulated CD4+ T-cells isolated from three genetically distinct blood donors were infected with chimeric viruses generated from patient viral sequences isolated at birth, NL4-3-00m06-eGFP and NL4-3-00m15-DsRED2. Infected cells were quantified by flow cytometry to calculate relative fitness (W) on days 3–7 post-infection. W of NL4-3-00m15-DsRED2 shown. <b>b)</b> Mean NL4-3-00m15-DsRED2 W from each donor (dots) with standard deviation (bars) over time. <b>c)</b> Competitions between NL4-3-00m06-eGFP and NL4-3-00m15-DsRED2 and the reciprocal NL4-3-00m06-DsRed2 and NL4-3-00m15-eGFP were repeated in U87.CD4.CCR5 cells. In both competitions, the W of NL4-3-00m15 in U87.CD4.CCR5 at Day 5 post-infection was not statistically different from the W calculated in PBMC at Day 7.</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "pbmc"], "article_id"=>693668, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chimera_fitness_in_PBMC_and_U87_CD4_CCR5_cells_/693668", "title"=>"Chimera fitness in PBMC and U87.CD4.CCR5 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048181"], "description"=>"<p><b>a)</b> Diagram of the HIV-1 NL4-3-MSS-eGFP/DsRED2 construct showing an expansion of the region bounded by EcoRI and XhoI and encompassing the code for Tat, Vpu, Rev, and Env. Introduced silent mutations are underlined. Sequence region utilized in this paper purple. <b>b)</b> HEK 293 cells transfected with either NL4-3-MSS-eGFP or NL4-3-MSS-DsRED2 were imaged by fluorescent microscopy (40×) at 48-hours post-transfection (b). <b>c)</b> Pelleted virions derived from <sup>35</sup>S- radiolabeled transfected cells were immunoprecipitated with HIV-Ig and the resulting proteins were separated by SDS-PAGE revealing bands corresponding to gp120 (Env) and p66 (RT) in wild-type, NL4-3-MSS-eGFP, and NL4-3-MSS-DsRED2, but not mock transfected cells. <b>d)</b> Virus stocks derived from NL4-3-MSS-eGFP (green line) and NL4-3-MSS-DsRED2 (red line) transfections were used to infect U87.CD4.CXCR4 cells. Virus replication kinetics were assayed using a <sup>3</sup>H-based RT assay at the indicated time-points. Mock transfected cell supernatant served as a control (black triangles).</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "infectious", "molecular", "clones", "fluorescence", "293t", "transfectants"], "article_id"=>693665, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_infectious_molecular_clones_results_in_fluorescence_in_293T_transfectants_and_generation_of_infectious_virions_/693665", "title"=>"Expression of infectious molecular clones results in fluorescence in 293T transfectants and generation of infectious virions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1048198"], "description"=>"<p>Viral stocks of eGFP chimeras were incubated with serial dilutions of a CD4 competitor (B4 Ab) or CCR5 competitor (2D7 Ab), and added to TZB-bl indicator cells. Though reduction in eGFP expression with increased competitor antibody could be visualized via microscopy <b>(a, b)</b> (40×), IC<sub>50</sub>s were calculated from luciferase activity assays, in triplicate. When IC<sub>50</sub> values were plotted against average relative fitness values, there was no correlation for CD4 affinity (<b>c</b>) (R<sup>2</sup> = 0.02970) or (<b>d</b>) CCR5 affinity (R<sup>2</sup> = 0.0001508) (dashed lines 95% CI).</p>", "links"=>[], "tags"=>["Evolutionary biology", "Evolutionary genetics", "population genetics", "microbiology", "Virology", "Viral transmission and infection", "Viral entry", "Viral vectors", "Immunodeficiency viruses", "Viral evolution", "Microbial evolution", "Infectious diseases", "Viral diseases", "hiv", "affinity", "cd4", "ccr5", "correlated"], "article_id"=>693682, "categories"=>["Medicine", "Biological Sciences"], "users"=>["S. Abigail Smith", "Charles Wood", "John T. West"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063094.g008", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chimera_affinity_for_CD4_or_CCR5_is_not_correlated_with_fitness_/693682", "title"=>"Chimera affinity for CD4 or CCR5 is not correlated with fitness.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-29 01:01:22"}

PMC Usage Stats | Further Information

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Relative Metric

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