Coinfections: Another Variable in the Herpesvirus Latency-Reactivation Dynamic

Abstract

Chronic viruses, such as herpesviruses, shape host physiology. These viruses modulate the inflammatory state of the immune system and have evolved to harness inflammation as a mechanism to regulate viral latency and reactivation. In this review, I examine some of the recent work demonstrating the important role of inflammation in the regulation of the herpesvirus life cycle and discuss recent work that implicates coinfection in the regulation of herpesvirus latency. Herpesviruses are a family of viruses that have closely evolved with their host species. Every vertebrate examined has at least one herpesvirus, and each herpesvirus is closely associated with one host species (1). In humans, more than 90% of the population is infected with at least one herpesvirus (2). This suggests that these viruses have evolved with their hosts over a long period of time and are well adapted to them. It also suggests that our immune systems have evolved in the company of these infections and are shaped by their durable presence.Herpesviruses establish lifelong chronic infections with periods of limited viral gene expression and no viral progeny production. This noncytopathic infection is termed latency. In the case of gammaherpesviruses, which are the focus of this review, latency is established primarily in B cells but also in macrophages and dendritic cells (1).Rather than being a static event, latency is quite dynamic. Even though chronic infection is usually associated with little to no disease, these viruses are undergoing brief periods of reactivation during which small amounts of virus are produced. Production of virus during latency is likely important for spread of the virus to new hosts, as well as maintenance of a viral reservoir in the host. However, these reactivation events are tightly controlled by the immune system, which forces the virus to return to latency. Both the delicate balance between viral reactivation and latency and the complex relationship between the host immune system and herpesviruses are important for understanding how viruses influence host physiology.We recently demonstrated not only that a mouse gammaherpesvirus (murine gammaherpesvirus 68 [MHV68; also known as ␥HV68 or MHV4]) modulates the immune system but also that subsequent infections with particular pathogens induce gammaherpesvirus reactivation from latency (3). These findings add another layer of complexity to our understanding of host-virus interactions and suggest that this relationship is modulated by coinfections. This has important implications for how herpesviruses shape immunity.

Environmental stressors may cause equine herpesvirus reactivation in captive Grévy’s zebras (Equus grevyi)

“…However, all herpesviruses share the ability to establish latent infections which can last for the lifetime of their hosts ( Carter, Wise & Flores, 2006 ). The time span of viral latency is characterized by absence of significant viral replication and minimal viral gene expression, despite presence of the viral genome in the nucleus of the infected cell ( White, Suzanne Beard & Barton, 2012 ; Reese, 2016 ). In contrast to human herpesviruses, reactivation of latent EHV infections and the associated physiological conditions are not well understood, but it is generally assumed that exposure to environmental stressors play a major role in the reactivation of latent viral infections ( Padgett et al, 1998 ; Glaser & Kiecolt-Glaser, 2005 ; Dunowska, 2014b ; Sebastiano et al, 2017 ).…”

Noninvasive Detection of Equid Herpesviruses in Fecal Samples

“…Herpesviruses remain primarily latent in host neural and lymphoid tissues (17). Viral latency is characterized by the absence of lytic viral replication and minimal, if any, viral gene expression, despite the presence of the viral genome in the nucleus of the infected cell (17,18). However, herpesviruses can be reactivated (17), leading to shedding of infectious virus into the environment.…”

The influence of dual infection with herpes and influenza viruses on the differential blood cell count of mice

“…These findings allow a different view on the understanding of host-virus interactions and suggest the mutual modulation of the immune response of organism to individual pathogens during the co-infection. This has important implications for the herpesvirus shaping of immunity (Reese, 2016). Recent studies identified a critical role of helminth-induced IL-4/ IL-13 and STAT6 activity in reactivation of latent gammaherpesvirus infection in macrophages, which indicates a conserved mechanism of innate immunomodulation in the context of virus-helminth co-infection (Osborne et al, 2014;Reese et al, 2014;Degarege and Erko, 2016).…”