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Coinfections: Another Variable in the Herpesvirus Latency-Reactivation Dynamic


Patient in training
Coinfections: Another Variable in the Herpesvirus Latency-Reactivation Dynamic

Open access

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 γHV68 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.

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Senior Member
This paper deals with an important subject, and a gap in current medical thinking. Unfortunately, it misses some points I consider important.

The first is the scale of the effect of latent infection. Too often we have doctors looking at antibodies and virions in peripheral blood to judge the effect of viral load. Latent infections do not result in cytolysis, so the number of infected cells does not correlate well with antibodies or virions released during this process.

This is especially important for EBV infection, where there are three different latent states, and two of these are not completely inactive. It is possible for a cell to replicate viral DNA without going on to cytolysis. If this is a B-cell responding to yet another infection via clonal expansion, multiple viral episomes inside the nuclear membrane can end up in both daughter cells after mitosis. The number of infected cells increases with very little evidence of active infection. This process can repeat until the discrepancy between antibody levels and number of infected cells becomes enormous. It is possible to directly measure the number of infected cells by multiple flow cytometry looking for specific epitopes. At present we have very little work showing how this relates to pathology.

I will point out that there has been some success in targeting EBV infected cells in individual MS patients. It doesn't matter, to my way of thinking, whether you think EBV "causes" the disease or not, depleting only infected cells provides a much finer granularity of intervention. Should the individual in question have an immune defect, depleting immune cells most vulnerable to this defect can correct an error in immune function without devastating the entire immune system.

If we knew what each type of immune cell was doing in states of health or pathology, including those carrying viral infections, we could adjust immune performance in a more rational way. Then we might have some idea what therapeutic interventions are actually doing to patients. Current practice is based on a great deal of general ignorance, and massive ignorance about the effect on any particular patient. Doctors have the habit of treating generic patients, and the damn patients have the habit of responding in idiosyncratic ways, even going so far as to die.