Elidamar Nunes de Carvalho Lima1, Rodrigo Sucupira Andrade Lima2, José Roberto Castilho Piqueira3, Maria Cecília Sucupira4, Michelle Camargo4, Juliana Galinskas4, Ricardo Sobhie Diaz5. 1. Telecommunication and Control Engineering Department, Engineering School, University of São Paulo, São Paulo, Brazil; Infectious Diseases Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil. Electronic address: elidamarnunes@usp.br. 2. Telecommunication and Control Engineering Department, Engineering School, University of São Paulo, São Paulo, Brazil. 3. Telecommunication and Control Engineering Department, Engineering School, University of São Paulo, São Paulo, Brazil. Electronic address: piqueira@lac.usp.br. 4. Infectious Diseases Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil. 5. Infectious Diseases Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil. Electronic address: rsdiaz@catg.com.br.
Abstract
OBJECTIVES: This study analyzed Protease-PR and Reverse Transcriptase-RT HIV-1 genomic information entropy metrics among patients under antiretroviral virologic failure, according to the numbers of virologic failures or resistance mutations. METHODS: For this purpose, we used genomic sequences from PR and RT of HIV-1 from a cohort of chronic patients followed up at São Paulo Hospital. RESULTS: Informational entropy proportionally increases with the number of antiretroviral virologic failures in PR and RT (p < .001). Affected regions of PR were related to catalytic and structural functions, such as Fulcrum (K20) Flap (M46) and Cantilever (A71). In RT, this occurred at Fingers (E44) and Palm (K219). Informational entropy increases according to the number of resistance mutations in PR and RT (p < .001). Higher PR entropy was proportional to the resistance mutation numbers in Fulcrum (L10), Active site (L24) Flap (M46), Cantilever (L63) and near Interface (L90). In RT, they related to regions responsible for protein stability such as Fingers (T39) and Palm (L100). CONCLUSIONS: The antiretroviral selective pressure affects HIV genomic informational entropy at the PR and RT regions, leading to the emergence of more unstable virions. Mapping the three-dimensional structure in these HIV-1 proteins is relevant to designing new antiretroviral targeting resistant strains.
OBJECTIVES: This study analyzed Protease-PR and Reverse Transcriptase-RT HIV-1 genomic information entropy metrics among patients under antiretroviral virologic failure, according to the numbers of virologic failures or resistance mutations. METHODS: For this purpose, we used genomic sequences from PR and RT of HIV-1 from a cohort of chronic patients followed up at São Paulo Hospital. RESULTS: Informational entropy proportionally increases with the number of antiretroviral virologic failures in PR and RT (p < .001). Affected regions of PR were related to catalytic and structural functions, such as Fulcrum (K20) Flap (M46) and Cantilever (A71). In RT, this occurred at Fingers (E44) and Palm (K219). Informational entropy increases according to the number of resistance mutations in PR and RT (p < .001). Higher PR entropy was proportional to the resistance mutation numbers in Fulcrum (L10), Active site (L24) Flap (M46), Cantilever (L63) and near Interface (L90). In RT, they related to regions responsible for protein stability such as Fingers (T39) and Palm (L100). CONCLUSIONS: The antiretroviral selective pressure affects HIV genomic informational entropy at the PR and RT regions, leading to the emergence of more unstable virions. Mapping the three-dimensional structure in these HIV-1 proteins is relevant to designing new antiretroviral targeting resistant strains.
Authors: Soo-Yon Rhee; Michael Boehm; Olga Tarasova; Giulia Di Teodoro; Ana B Abecasis; Anders Sönnerborg; Alexander J Bailey; Dmitry Kireev; Maurizio Zazzi; Robert W Shafer Journal: Pathogens Date: 2022-05-05