The effects of immunosuppression on SARS-CoV-2 persistence, virus genetic diversity and clinical outcomes of COVID-19

ABSTRACT One of the biggest challenges for the development of Coronavirus Disease 2019 (COVID-19) vaccines and therapeutics is the emergence of SARS-CoV-2 variants with immune-escape or resistance mutations. Multiple evidence points to the chronic infection of immunocompromised hosts, especially individuals with hematologic malignancies, as one of the main mechanisms for the emergence and spread of these variants. While most people with a competent immune system successfully clear SARS-CoV-2 infection within days, some patients with hematologic malignancies and weakened immunity get persistently infected for months with virus replicating often at high titers. As for other RNA viruses, SARS-CoV-2 replication can lead to the rapid accumulation of mutations over time. Thus, persistent infection of an immunocompromised host provides the timeframe during which the virus accumulates more genetic mutations than expected from individual infections without the need of transmission to another host. Moreover, these individuals could remain contagious for longer periods of time and sustain transmission to the community of variants potentially associated with virus fitness advantages, including increased transmissibility or resistance to COVID-19 vaccines or treatments. Which host immune background enables chronic infection, what specific selection acts on the virus, and what effects on the host do emerging mutations exert over the course of the disease are currently unknown. Moreover, there are no tools that allow the early identification of subjects that will develop prolonged infection. We hypothesize that specific defects in B and T cell populations that favor prolonged infection can be leveraged for the development of an early prediction tool to identify subjects with protracted infection where the virus is accumulating mutations. To address this, we will integrate patient level and epidemiological data with immune profiling and SARS-CoV-2 deep sequencing to: (1) determine the immune defects linked to prolonged replication or acute disease; (2) ascertain the effect of different immunosuppressive conditions and therapeutics on SARS-CoV-2 genetic diversity within the infected host. Our studies will advance our understanding of the immune mechanisms involved in SARS-CoV2 persistence in the immunocompromised host and inform the development of optimal therapies and public health interventions to prevent the emergence and spread of new viral variants. This approach, if successful, is also relevant to other respiratory viruses.