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In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations with<jats:italic>P<\/jats:italic>values of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations was experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8<jats:sup>+<\/jats:sup>T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8<jats:sup>+<\/jats:sup>T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8<jats:sup>+<\/jats:sup>T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.<\/jats:p>","DOI":"10.1128\/jvi.01547-06","type":"journal-article","created":{"date-parts":[[2007,1,4]],"date-time":"2007-01-04T06:28:28Z","timestamp":1167892108000},"page":"2887-2898","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Dual Selection Pressure by Drugs and HLA Class I-Restricted Immune Responses on Human Immunodeficiency Virus Type 1 Protease"],"prefix":"10.1128","volume":"81","author":[{"given":"Sandra M.","family":"Mueller","sequence":"first","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"},{"name":"German Competence Network on HIV\/AIDS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Schaetz","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"},{"name":"German Competence Network on HIV\/AIDS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Eismann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Bauerle","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Schmitt-Haendle","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hauke","family":"Walter","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany"},{"name":"German Competence Network on HIV\/AIDS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Korn","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Center, University of Erlangen-Nuremberg, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"Spriewald","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen G.","family":"Harrer","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Harrer","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany"},{"name":"German Competence Network on HIV\/AIDS"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200103300-00009"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.7.4094"},{"key":"e_1_3_2_4_2","unstructured":"Boehringer Ingelheim Pharmaceuticals. 19 April 2005 posting date. 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