Antiviral resistance and persistent replication of cytomegalovirus and SARS-CoV-2 in immunocompromised patients

Abstract

[eng] The main objectives of this thesis are to study the opportunistic infection caused by human cytomegalovirus and SARS-CoV-2 inquiring persistent infection and antiviral resistance. These major objectives can be further divided into: 1. Characterization of mutations associated with antiviral resistance in immunocompromised patients with refractory human cytomegalovirus infection. 1.1. Genotypic antiviral resistance testing of human cytomegalovirus target genes of conventional and new antiviral therapies by Sanger and next generation sequencing. 1.2. Phenotypic studies of uncharacterized mutations found genotypically in clinical samples by bacmid technologies, to determine the antiviral susceptibility and the replicative capacity of each individual mutation. 1.3. Searching for baseline resistant mutations before the administration of new therapies to prevent antiviral treatment failure. 1.4. Determining the incidence of cytomegalovirus antiviral resistance mutations, natural polymorphisms, and uncharacterized genetic variants in immunocompromised patients with clinically resistant cytomegalovirus infection. 2. Quantification of SARS-CoV-2 normalized viral loads in respiratory samples to study the dynamics of total viral RNA. 3. Determination of SARS-CoV-2 replicative capacity during the infection course by the presence of subgenomic RNA, and its broad applicability on the patients’ clinical monitoring. 4. Assessment of patients with persistent SARS-CoV-2 replication and/or severe COVID-19 treated with remdesivir. 5. Search of mutations associated with remdesivir failure by next-generation sequencing in severe COVID-19 patients.

[spa] Esta tesis estudia la caracterización genotípica y fenotípica de mutaciones de resistencia a los anvitivirales, asi como la replicación viral persistente, en el paciente inmunocomprometido. En concreto se estudia la infección por citomegalovirus por su alta prevalencia en la población y por su alta mortalidad en pacientes imunocomprometidos, y la infección emergente por SARS-CoV-2 debido a su rápida diseminación causante de la pandemia COVID-19, la cual ha afectado especialmente a este tipo de paciente condicionando a una replicación prolongada, al uso de fármacos antivirales y la aparición de resistencias.