title: Selection pressure in CD8⁺ T-cell epitopes in the pol gene of HIV-1 infected individuals in Colombia. A bioinformatic approach.
abstract: One of the main characteristics of the human immunodeficiency virus is its genetic variability and rapid adaptation to changing environmental conditions. This variability, resulting from the lack of proofreading activity of the viral reverse transcriptase, generates mutations that could be fixed either by random genetic drift or by positive selection. Among the forces driving positive selection are antiretroviral therapy and CD8+ T-cells, the most important immune mechanism involved in viral control. Here, we describe mutations induced by these selective forces acting on the pol gene of HIV in a group of infected individuals. We used Maximum Likelihood analyses of the ratio of non-synonymous to synonymous mutations per site (dN/dS) to study the extent of positive selection in the protease and the reverse transcriptase, using 614 viral sequences from Colombian patients. We also performed computational approaches, docking and algorithmic analyses, to assess whether the positively selected mutations affected binding to the HLA molecules. We found 19 positively-selected codons in drug resistance-associated sites and 22 located within CD8+ T-cell epitopes. A high percentage of mutations in these epitopes has not been previously reported. According to the docking analyses only one of those mutations affected HLA binding. However, algorithmic methods predicted a decrease in the affinity for the HLA molecule in seven mutated peptides. The bioinformatics strategies described here are useful to identify putative positively selected mutations associated with immune escape but should be complemented with an experimental approach to define the impact of these mutations on the functional profile of the CD8+ T-cells.
authors: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, 050010, Colombia. liloacevedo@gmail.com.
authors: Liliana
authors: L
authors: Acevedo-Sáenz
authors: Programa de Estudio y Control de Enfermedades Tropicales-PECET, Universidad de Antioquia, Medellín, 050010, Colombia. rodrigo.ochoa@udea.edu.co.
authors: Rodrigo
authors: R
authors: Ochoa
authors: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, 050010, Colombia. maria.rugeles@udea.edu.co.
authors: Maria Teresa
authors: MT
authors: Rugeles
authors: Centro de Análisis Molecular, Bogotá D.C., 111156, Colombia. patolaya@etb.net.co.
authors: Patricia
authors: P
authors: Olaya-García
authors: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, 050010, Colombia. pvelilla@gmail.com.
authors: Paula Andrea
authors: PA
authors: Velilla-Hernández
authors: Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, 050010, Colombia. francisco.diaz@udea.edu.co.
authors: Francisco J
authors: FJ
authors: Diaz
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003105:Colombia; D019295:Computational Biology; D024882:Drug Resistance, Viral; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D011485:Protein Binding; D012641:Selection, Genetic; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D044966:Anti-Retroviral Agents; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D054302:pol Gene Products, Human Immunodeficiency Virus; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase