Estimating the Fitness Cost of Escape from HLA Presentation in HIV-1 Protease and Reverse Transcriptase
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{"title"=>"Estimating the fitness cost of escape from hla presentation in HIV-1 protease and reverse transcriptase", "type"=>"journal", "authors"=>[{"first_name"=>"Rafal", "last_name"=>"Mostowy", "scopus_author_id"=>"36139106800"}, {"first_name"=>"Roger D.", "last_name"=>"Kouyos", "scopus_author_id"=>"14023112100"}, {"first_name"=>"Ilka", "last_name"=>"Hoof", "scopus_author_id"=>"24597293400"}, {"first_name"=>"Trevor", "last_name"=>"Hinkley", "scopus_author_id"=>"23050628100"}, {"first_name"=>"Mojgan", "last_name"=>"Haddad", "scopus_author_id"=>"35955943600"}, {"first_name"=>"Jeannette M.", "last_name"=>"Whitcomb", "scopus_author_id"=>"7005226522"}, {"first_name"=>"Christos J.", "last_name"=>"Petropoulos", "scopus_author_id"=>"35464017000"}, {"first_name"=>"Can", "last_name"=>"Keşmir", "scopus_author_id"=>"6701789184"}, {"first_name"=>"Sebastian", "last_name"=>"Bonhoeffer", "scopus_author_id"=>"7005099220"}], "year"=>2012, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-84863680755", "pui"=>"365220683", "pmid"=>"22654656", "issn"=>"1553734X", "isbn"=>"1553-7358 (Electronic)\r1553-734X (Linking)", "doi"=>"10.1371/journal.pcbi.1002525", "sgr"=>"84863680755"}, "id"=>"7ff61933-9d92-3903-94af-a072ebdc0a38", "abstract"=>"Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of in vitro replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower in vitro replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general.", "link"=>"http://www.mendeley.com/research/estimating-fitness-cost-escape-hla-presentation-hiv1-protease-reverse-transcriptase", "reader_count"=>22, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>9, "Student > Master"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>9, "Student > Master"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>7, "Medicine and Dentistry"=>2, "Physics and Astronomy"=>1, "Social Sciences"=>1, "Computer Science"=>2, "Immunology and Microbiology"=>3, "Linguistics"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Computer Science"=>{"Computer Science"=>2}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "reader_count_by_country"=>{"United States"=>1, "India"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/327307", "https://ndownloader.figshare.com/files/327357"], "description"=>"<div><p>Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of <em>in vitro</em> replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower <em>in vitro</em> replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general.</p> </div>", "links"=>[], "tags"=>["estimating", "hla", "hiv-1", "protease", "transcriptase"], "article_id"=>124603, "categories"=>["Genetics", "Immunology", "Evolutionary Biology"], "users"=>["Rafal Mostowy", "Roger D. Kouyos", "Ilka Hoof", "Trevor Hinkley", "Mojgan Haddad", "Jeannette M. Whitcomb", "Christos J. Petropoulos", "Can Keşmir", "Sebastian Bonhoeffer"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002525.s001", "https://dx.doi.org/10.1371/journal.pcbi.1002525.s002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Estimating_the_Fitness_Cost_of_Escape_from_HLA_Presentation_in_HIV_1_Protease_and_Reverse_Transcriptase/124603", "title"=>"Estimating the Fitness Cost of Escape from HLA Presentation in HIV-1 Protease and Reverse Transcriptase", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-24 01:16:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/632901"], "description"=>"<p>(<b>Top row</b>) Effect of mutations on binding affinity to HLA-A molecules according to two alternative epitope definitions (absolute criterion: , relative criterion: ). In both cases we observed a significant correlation between the fitness of single mutants and the impairment of binding to HLA-A (absolute criterion: , ; relative criterion: , ). Each datapoint corresponds to a single amino acid substitution in the genetic region restricted by HLA alleles of the corresponding locus, A or B. Note, that if multiple HLA molecules were affected by a single mutation at a given locus, the strongest impairment was plotted here. (<b>Bottom row</b>) Effect of mutations on binding affinity to HLA-B molecules for the two alternative epitope definitions (absolute criterion: , relative criterion: ). Here, no significant correlation between the quantities in question was found (absolute criterion: ; relative criterion: ). For the sake of illustration, the blue line shows the best fit of a linear regression and the 95% confidence interval.</p>", "links"=>[], "tags"=>["mutations", "impair"], "article_id"=>303390, "categories"=>["Genetics", "Immunology", "Evolutionary Biology"], "users"=>["Rafal Mostowy", "Roger D. Kouyos", "Ilka Hoof", "Trevor Hinkley", "Mojgan Haddad", "Jeannette M. Whitcomb", "Christos J. Petropoulos", "Can Keşmir", "Sebastian Bonhoeffer"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002525.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cost_of_mutations_which_impair_the_HLA_binding_/303390", "title"=>"Cost of mutations which impair the HLA-binding.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 00:56:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/632969"], "description"=>"<p>The distribution of replicative fitness effects (DFE) of random mutations in HIV-1 (green) will differ from the corresponding distribution of mutations derived from the patient population (blue/orange) as the latter will feature only mutations which have undergone selection. Mutations with a particularly high replicative cost (i.e., low replicative capacity) will have a low probability of being present in the patient-derived data because they will persist at very low frequencies in the virus population. However, escape mutations carry an additional benefit of avoiding being killed by the immune system and therefore are expected to have a higher <i>in vivo</i> fitness, which allows for persistence in spite of a lower replicative capacity. For this reason, even if the DFE of escape and non-escape mutations are identical, the escape mutations derived from the patient population (blue) may appear to have on average a lower replicative capacity than the non-escape mutations derived from the patient population (orange).</p>", "links"=>[], "tags"=>["observed", "hla"], "article_id"=>303460, "categories"=>["Genetics", "Immunology", "Evolutionary Biology"], "users"=>["Rafal Mostowy", "Roger D. Kouyos", "Ilka Hoof", "Trevor Hinkley", "Mojgan Haddad", "Jeannette M. Whitcomb", "Christos J. Petropoulos", "Can Keşmir", "Sebastian Bonhoeffer"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002525.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Population_effect_in_the_observed_cost_of_escape_from_HLA_presentation_/303460", "title"=>"Population effect in the observed cost of escape from HLA presentation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 00:57:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/633052"], "description"=>"<p>Correlation between fitness of single mutations and impairment of binding to rare (lower than 0.5%, see Materials & Methods) HLA-A molecules (absolute criterion: , relative criterion: ). We observed a significant correlation for both epitope definitions (absolute criterion: , ; relative criterion: , ). For the sake of illustration, the blue line shows the best fit of a linear regression and the 95% confidence interval.</p>", "links"=>[], "tags"=>["hla-a"], "article_id"=>303542, "categories"=>["Genetics", "Immunology", "Evolutionary Biology"], "users"=>["Rafal Mostowy", "Roger D. Kouyos", "Ilka Hoof", "Trevor Hinkley", "Mojgan Haddad", "Jeannette M. Whitcomb", "Christos J. Petropoulos", "Can Keşmir", "Sebastian Bonhoeffer"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002525.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cost_of_escape_from_rare_HLA_A_alleles_/303542", "title"=>"Cost of escape from rare HLA-A alleles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 00:59:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/633129"], "description"=>"<p>(<b>Top row</b>) Effect of mutations on binding affinity to 10 most protective HLA molecules according to two alternative epitope definitions (absolute criterion: , relative criterion: ). Protectiveness of alleles was characterized based on the relative hazard for AIDS progression (see Materials & Methods). A significant correlation between the fitness of single mutants and the impairment of binding to the most protective HLA molecules was observed (absolute criterion: , ; relative criterion: , ). (<b>Bottom row</b>) Effect of mutations on binding affinity to 10 most non-protective HLA molecules according to two alternative epitope definitions (absolute criterion: , relative criterion: ). In this case, no significant correlation between the fitness of single mutants and the impairment of binding to the most non-protective HLA molecules was found (absolute criterion: ; relative criterion: ). For the sake of illustration, the blue line shows the best fit of a linear regression and the 95% confidence interval.</p>", "links"=>[], "tags"=>["non-protective", "hla"], "article_id"=>303615, "categories"=>["Genetics", "Immunology", "Evolutionary Biology"], "users"=>["Rafal Mostowy", "Roger D. Kouyos", "Ilka Hoof", "Trevor Hinkley", "Mojgan Haddad", "Jeannette M. Whitcomb", "Christos J. Petropoulos", "Can Keşmir", "Sebastian Bonhoeffer"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002525.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cost_of_escape_from_the_protective_and_the_non_protective_HLA_alleles_/303615", "title"=>"Cost of escape from the protective and the non-protective HLA alleles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:00:15"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Computational biology", "average_usage"=>[375, 629, 760, 889, 1000, 1110, 1203, 1298, 1399, 1492, 1603, 1699, 1774, 1855, 1918, 1998, 2062, 2152, 2227, 2312, 2378, 2461, 2528, 2600, 2664]}, {"subject_area"=>"/Biology and life sciences/Evolutionary biology", "average_usage"=>[366, 574, 695, 795, 885, 973, 1063, 1148, 1233, 1319, 1389, 1459, 1533, 1611, 1685, 1754, 1820, 1882, 1937, 2001, 2071, 2129, 2219, 2273, 2335]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[333, 576, 707, 814, 908, 1004, 1104, 1197, 1280, 1370, 1449, 1531, 1603, 1673, 1742, 1817, 1886, 1954, 2025, 2098, 2171, 2234, 2304, 2365, 2431]}, {"subject_area"=>"/Biology and life sciences/Microbiology", "average_usage"=>[339, 580, 709, 814, 907, 1003, 1095, 1190, 1286, 1375, 1466, 1546, 1622, 1694, 1765, 1830, 1902, 1978, 2054, 2122, 2194, 2269, 2330, 2388, 2460]}, {"subject_area"=>"/Biology and life sciences/Organisms", "average_usage"=>[331, 557, 677, 777, 868, 960, 1050, 1136, 1223, 1307, 1390, 1466, 1536, 1603, 1673, 1741, 1814, 1889, 1954, 2028, 2096, 2164, 2233, 2305, 2362]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[312, 547, 668, 769, 861, 953, 1046, 1135, 1224, 1307, 1388, 1464, 1536, 1606, 1676, 1744, 1812, 1882, 1954, 2020, 2089, 2155, 2218, 2282, 2344]}]}
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