Redefining Chronic Viral Infection

Abstract

Viruses that cause chronic infection constitute a stable but little-recognized part of our metagenome: our virome. Ongoing immune responses hold these chronic viruses at bay while avoiding immunopathologic damage to persistently infected tissues. The immunologic imprint generated by these responses to our virome defines the normal immune system. The resulting dynamic but metastable equilibrium between the virome and the host can be dangerous, benign, or even symbiotic. These concepts require that we reformulate how we assign etiologies for diseases, especially those with a chronic inflammatory component, as well as how we design and interpret genome-wide association studies, and how we vaccinate to limit or control our virome.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Following the idea that chronic infections require an equilibrium between control of viral replication and the level of immune-mediated pathology caused by the persisting T-cell responses 22 , we argue and provide evidence that functional adaptation, specialization, and the acquisition of stable phenotypes, rather than exhaustion, are the driving forces that determine T-cell response in chronic infections. Thus, we posit that the phenotype of exhausted T-cells actually reflects a finely tuned effector population that is optimized to fulfill a certain level of effector function and pathogen control without causing overwhelming immunopathology.…”

“…To achieve this, aggressive mechanisms are engaged at the risk of collateral tissue damage. We consider that the immune system adopts a different strategy in persisting infections that is driven by the need to balance pathogen control and tissue damage 22 . So far, the reduced ability of T-cells to produce cytokines in chronic infections has been seen as a sign of deteriorating T-cell function but this phenotype could also simply represent an effector stage that is optimized to cause less inflammation and immunopathology than normal effector T-cells.…”

Latent herpesvirus infection arms NK cells

“…Therefore, it is possible that viral reactivation events (productive or abortive, both of which are encompassed in latency as we use the term here) provide the driving force behind the observed immune activation in the host. 19 Future experiments that use MuHV-4 mutants with specific defects in the ability to reactivate will allow us to dissect the contribution of these components of chronic herpesvirus infection to immune modulation during latency.…”

“…This hypothesis was formed on the basis of the previous observation that latent herpesviruses have multiple stimulatory effects on the host immune system. 18,19 We tested this idea using Murid herpesvirus 4 (MuHV-4, also known as murine gammaherpesvirus-68), a natural pathogen in wild mice 20 that is closely related to the human viruses Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus. MuHV-4, like all herpesviruses, establishes life-long latent infection (carriage of the viral genome in latently infected cells punctuated by intermittent reactivation) in its hosts.…”

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

“…Taking into account that at least 90% of the human population is infected with at least one herpesvirus, and herpesvirus infection is largely asymptomatic in immunocompetent individuals, it is likely that herpesviruses provide some benefit to the host (Virgin et al 2009). It was initially thought that CMV latency was a transcriptionally quiescent phase; however, recent evidence shows several proteins and at least one noncoding RNA are transcribed during latency, and serve a variety of functions including maintenance of latency, immune evasion (discussed in more depth in the review by Jackson et al in this issue), and genome maintenance (Sinclair and Reeves 2013).…”