Evaluating Env-specific antibodies for the diagnosis and treatment of complex human diseases

Human endogenous retroviruses (HERV) are highly repetitive sequences that are remnants of viral infections successfully integrated in the genome. Aberrant expression of HERV envelope (Env) proteins is frequent in cancer, autoimmunity, neurodegeneration, and infection and has been associated with antibody responses. However, we do not know if all HERV Env proteins contribute to antibody responses or what the prognostic impact of HERV Env-specific antibodies is. Thus, the objectives of this proposal are to i) implement a high-throughput screening platform for HERV Env-specific antibodies and ii) develop a bioinformatics approach to identify the HERV insertions producing Env proteins. To achieve these goals, HEK293T cell lines overexpressing 10 different HERV Env proteins will be generated and used to quantify the abundance of Env-specific antibodies in serum from thousands of cancer, autoimmunity, and infection patients. With this work, we will determine if antibody responses to Env proteins are disease-specific and evaluate the impact of sex, age, and ethnicity on Env antibody titres. Following this, we will build a pangenome reference of HERV sequences in the human population to evaluate the polymorphism of HERV insertions. This database of HERV insertions will be used in combination with highly targeted sequencing (Amplicon-seq) and epigenomics to precisely identify the HERV insertions that are active in pathologies and produce Env proteins. Finally, we will analyse publicly available datasets to evaluate the impact of HERV Env expression on disease progression and survival. In addition to deepening our understanding of several human pathologies, this work could have important impacts on the diagnosis and treatment of complex human diseases.t