# Viral evolution during primary infection in immunocompromised hosts

## TL;DR

This study explores how immune deficiencies in individuals affect the speed of viral evolution during primary infections.

## Contribution

The paper introduces a mechanistic immunological model to analyze how different immunodeficiencies influence within-host viral evolution.

## Key findings

- Immunodeficiencies in neutrophils and interferon initially speed viral evolution but result in lower mutation frequencies by infection clearance.
- T cell deficiencies slow viral evolution in persistent infections, while interleukin-6 and macrophage deficiencies speed it up.
- Positive epistatic interactions from immune responses accelerate evolution of mutations that help viruses evade immunity and enter cells.

## Abstract

The immune response to viral infection is a delicate balance. By perturbing this balance, immunodeficiencies are expected to influence within-host viral evolution. Indeed, the presence of immunocompromised hosts has been argued to be a source of novel viral variants in some infectious diseases, including SARS-CoV-2. However, these arguments rest upon between-host models and so the role of immunodeficiencies on within-host evolution in primary infections is poorly understood. Using a mechanistic immunological model, here we consider how different immunodeficiencies shape the orchestration of the immune response during primary infection. We study how this alters the viral fitness landscape, thus speeding and slowing viral evolution. We show that during acute infections, while immunodeficiencies in neutrophils and interferon initially speed viral evolution, by the time the infection is cleared, mutations are at lower frequencies than in immunocompetent hosts. In persistent infections, we show that while T cell deficiencies slow viral evolution, interleukin-6 and macrophage deficiencies speed viral evolution. Finally, we show that positive epistatic interactions arising due to the immunological response will accelerate the evolution of viral mutations affecting the ability of virions to evade different aspects of the immune response and to enter host cells.

A robust immune response to viral infections is key to host protection. Upon first exposure, the immune system activates an elaborate response involving innate, adaptive, and humoral immunity. An inadequate or poorly regulated immune response, as observed in immunocompromised individuals, can result in a reduced ability to clear the virus, prolonging infection and potentially altering viral evolution. Here, we use a comprehensive mechanistic model of the immune response to a primary respiratory viral infection to study how immunodeficiencies affect the speed of within-host viral evolution. Our results show when perturbing the multiple interacting networks regulating the immune response leads to stronger selection for specific mutations, and when it does not. Overall, our study helps to untangle the interplay between the orchestration of immune responses and viral evolution in immunocompetent and immunocompromised hosts.