Viruses can persistently infect differentiated cells through regulation of expression of both their own genes and those of the host cell, thereby evading detection by the host’s immune system and achieving residence in a non-lytic state. Models in vitro with cell lines are useful tools in understanding the mechanisms associated with the establishment of viral persistence. In particular, a model to study respiratory syncytial virus (RSV) persistence in a murine macrophage-like cell line has been established. Compared to non-infected macrophages, macrophages persistently infected with RSV show altered expression both of genes coding for cytokines and trans-membrane proteins associated with antigen uptake and of genes related to cell survival. The biological changes associated with altered gene expression in macrophages as a consequence of persistent RSV infection are summarized.

Type-I interferon (IFN-I) production is an early response to viral infection and pathogenic viruses have evolved multiple strategies to evade this cellular defense. Some viruses can establish and maintain persistent infections by altering the IFN-I signaling pathway. Here, we studied IFN-I synthesis and response in an in vitro model of persistent infection by respiratory syncytial virus (RSV) in a murine macrophage-like cell line. In this model, interferon regulatory factor 3 was constitutively active and located at nuclei of persistently infected cells, inducing expression of IFN-beta mRNA and protein. However, persistently infected macrophages did not respond in an autocrine manner to the secreted-IFN-beta or to recombinant-IFN-beta, since phosphorylated-STAT1 was not detected by western blot and transcription of the interferon-stimulated genes (ISGs) Mx1 and ISG56 was not induced. Treatment of non-infected macrophages with supernatants from persistently infected cells induced STAT1 phosphorylation and ISGs expression, mediated by the IFN-I present in the supernatants, because blocking the IFN-I receptor inhibited STAT1 phosphorylation. Results suggest that the lack of autocrine response to IFN-I by the host cell may be one mechanism for maintenance of RSV persistence. Furthermore, STAT1 phosphorylation and ISGs expression induced in non-infected cells by supernatants from persistently infected macrophages suggest that RSV persistence may trigger a proinflammatory phenotype in non-infected cells as part of the pathogenesis of RSV infection.

Emerging human coronaviruses, including the recently identified SARS-CoV-2, are relevant respiratory pathogens due to their potential to cause epidemics with high case fatality rates, although endemic coronaviruses are also important for immunocompromised patients. Long-term coronavirus infections had been described mainly in experimental models, but it is currently evident that SARS-CoV-2 genomic-RNA can persist for many weeks in the respiratory tract of some individuals clinically recovered from coronavirus infectious disease-19 (COVID-19), despite a lack of isolation of infectious virus. It is still not clear whether persistence of such viral RNA may be pathogenic for the host and related to long-term sequelae.

Respiratory RNA viruses are a major cause of acute lower respiratory tract infections and contribute substantially to hospitalization among infants, elderly, and immunocompromised. Complete viral clearance from acute infections is not always achieved, leading to persistence. Certain chronic respiratory diseases like asthma and chronic obstructive pulmonary disease have been associated with persistent infection by human respiratory syncytial virus and human rhinovirus, but it is still not clear whether RNA viruses really establish long-term infections as it has been recognized for DNA viruses as human bocavirus and adenoviruses. Herein, we summarize evidence of RNA virus persistence in the human respiratory tract, as well as in some animal models, to highlight how long-term infections might be related to development and/or maintenance of chronic respiratory symptoms.