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Maps of CTL epitopes on HIV-1 protein sequences reveal that defined epitopes tend to cluster. Here we integrate the global sequence and immunology databases to systematically explore the relationship between HIV-1 amino acid sequences and CTL epitope distributions. CTL responses to five HIV-1 proteins, Gag p17, Gag p24, reverse transcriptase (RT), Env, and Nef, have been particularly well characterized in the literature to date. Through comparing CTL epitope distributions in these five proteins to global protein sequence alignments, we identified distinct characteristics of HIV amino acid sequences that correlate with CTL epitope localization. First, experimentally defined HIV CTL epitopes are concentrated in relatively conserved regions. Second, the highly variable regions that lack epitopes bear cumulative evidence of past immune escape that may make them relatively refractive to CTLs: a paucity of predicted proteasome processing sites and an enrichment for amino acids that do not serve as C-terminal anchor residues. Finally, CTL epitopes are more highly concentrated in alpha-helical regions of proteins. Based on amino acid sequence characteristics, in a blinded fashion, we predicted regions in HIV regulatory and accessory proteins that would be likely to contain CTL epitopes; these predictions were then validated by comparison to new sets of experimentally defined epitopes in HIV-1 Rev, Tat, Vif, and Vpr.<\/jats:p>","DOI":"10.1128\/jvi.76.17.8757-8768.2002","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T19:36:19Z","timestamp":1033500979000},"page":"8757-8768","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":206,"title":["Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation"],"prefix":"10.1128","volume":"76","author":[{"given":"Karina","family":"Yusim","sequence":"first","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico 87545"},{"name":"Santa Fe Institute, Santa Fe, New Mexico 87501"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Kesmir","sequence":"additional","affiliation":[{"name":"Theoretical Biology Group, Utrecht University, 3584 CH Utrecht, The Netherlands"},{"name":"Center for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark, DK-2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Gaschen","sequence":"additional","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico 87545"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marylyn M.","family":"Addo","sequence":"additional","affiliation":[{"name":"Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Altfeld","sequence":"additional","affiliation":[{"name":"Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Brunak","sequence":"additional","affiliation":[{"name":"Center for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark, DK-2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Chigaev","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Detours","sequence":"additional","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico 87545"},{"name":"Santa Fe Institute, Santa Fe, New Mexico 87501"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bette T.","family":"Korber","sequence":"additional","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico 87545"},{"name":"Santa Fe Institute, Santa Fe, New Mexico 87501"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(99)00171-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.1781"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/35030124"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.5.2743"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(97)00286-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9629945"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1159\/000053995"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.263"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.4.1898"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.4049\/jimmunol.136.7.2498","volume":"136","year":"1986","unstructured":"Berkower, I., G. 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