Respuesta de los linfocitos T CD8+ a epítopes mutados restringidos al HLA-A*02:01 derivados de la proteína Gag de variantes de VIH-1 circulantes en Medellín, Colombia

ABSTRACT: BACKGROUND: A previous study, in a cohort of patients infected with HIV-1 from the city of Medellín, it was shown the adaptation of circulating strains of HIV-1 to the most prevalent HLA-I molecules in the population (HLA-A*02:01) through the identification of mutations under positive selection located in epitopes derived from the Gag protein (GC9, SL9). Furthermore, through an in silico prediction, it was evaluated whether the mutations found had a higher or lower affinity to the HLA-I. Although this strategy allowed predicting the interaction between mutated peptides and HLA-I, the functional response of CD8+ T-cells that these peptides can induce is unknown. METHODOLOGY: Peripheral blood mononuclear cells from 12 HIV-1+ patients with the HLA-A*02:01 allele, were stimulated with the different mutated and wild type peptides derived from the GC9 and SL9 epitopes. The functional profile of CD8+ T-cells was evaluated using flow cytometry and the quality of the response was analyzed according to their number of functions and the polyfunctionality index using the SPICE and Funky Cells Toolbox softwares. RESULTS: For GC9 peptide, the percentage of monofunctional cells after stimulation with the S54T peptide was significantly lower compared with the low affinity S54A/E55G peptide. Also, a higher polyfunctionality index (PI) for S54T was significantly higher in comparison with S54A/E55G peptide. For SL9 peptide, we observed a higher frequency of CD107a+ and CD107a+ granzyme B+ CD8+ T-cells and a higher PI in response to the WT peptide in comparison with the mutated form Y79F/T84V/L85F associated with a lower HLA-I binding affinity. Moreover, we observed a higher polyfunctional response to the mutated variants S54A and Y79F/T84V/L85F in individuals with a longer treatment duration. CONCLUSIONS: Our results suggest that i) a lower HLA-I binding affinity of mutated epitopes might be associated with a lower cytotoxic profile and lower polyfunctionality in CD8+ T-cells, and ii) the functional profile of specific CD8+ T-cells to mutated epitopes in individuals under cART is maintained or even expanded.

• Autores: Sánchez Martínez, Alexandra
• Fecha de publicación: 2020
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/19288
• Acceso en línea: http://hdl.handle.net/10495/19288
• Palabra clave: Linfocitos T CD8-positivos; CD8-Positive T-lymphocytes; VIH-1; HIV-1; Productos del gen gag; Gene products, gag; Epítopos de linfocito T; Epitopes, T-lymphocyte; Antígenos HLA-A; HLA-A antigens; http://id.nlm.nih.gov/mesh/D018414; http://id.nlm.nih.gov/mesh/D015497; http://id.nlm.nih.gov/mesh/D015683; http://id.nlm.nih.gov/mesh/D018984; http://id.nlm.nih.gov/mesh/D015234
• Rights: embargoedAccess
• License: http://creativecommons.org/licenses/by-nc-nd/2.5/co/