Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich, Switzerland
Christian Wandell Thorball
School of Life Sciences, École Polytechnique, Fédérale de Lausanne, Switzerland; Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
School of Life Sciences, École Polytechnique, Fédérale de Lausanne, Switzerland; Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Jürg Böni
Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich, Switzerland
Sabine Yerly
Laboratory of Virology, Geneva University Hospital, University of Geneva, Geneva, Switzerland
Matthieu Perreau
Division of Immunology and Allergy, University Hospital Lausanne, University of Lausanne, Lausanne, Switzerland
Hans H Hirsch
Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland; Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital Basel, Basel, Switzerland; Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich, Switzerland
Maria Christine Thurnheer
University Clinic of Infectious Diseases, University Hospital of Bern, University of Bern, Bern, Switzerland
Manuel Battegay
Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital Basel, Basel, Switzerland
Matthias Cavassini
Department of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
Enos Bernasconi
Division of Infectious Diseases, Regional Hospital, Lugano, Switzerland
Huldrych F Günthard
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich, Switzerland
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Medical Virology, Swiss National Center for Retroviruses, University of Zurich, Zurich, Switzerland
Background: Considering the remaining threat of drug-resistantmutations (DRMs) to antiretroviral treatment (ART) efficacy, we investigated how the selective pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes drives certain DRMs’ emergence and retention. Methods: We systematically screened DRM:HLA class I allele combinations in 3997 ART-naïve Swiss HIV Cohort Study (SHCS) patients. For each pair, a logistic regression model preliminarily tested for an association with the DRM as the outcome. The three HLA:DRM pairs remaining after multiple testing adjustment were analyzed in three ways: cross-sectional logistic regression models to determine any HLA/infection time interaction, survival analyses to examine if HLA type correlated with developing specific DRMs, and via NetMHCpan to find epitope binding evidence of immune escape. Results: Only one pair, RT-E138:HLA-B18, exhibited a significant interaction between infection duration and HLA. The survival analyses predicted two pairs with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075–1.273]; p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523–42.318]; p-value<0.001). The same two pairs were also predicted by netMHCpan to have epitopic binding. Conclusions: We identified DRM:HLA pairs where HLA presence is associated with the presence or emergence of the DRM, indicating that the selective pressure for these mutations alternates direction depending on the presence of these HLA alleles. Funding: Funded by the Swiss National Science Foundation within the framework of the SHCS, and the University of Zurich, University Research Priority Program: Evolution in Action: From Genomes Ecosystems, in Switzerland.