Herpesviruses - not all bad?

The name herpes comes from the Greek word ‘herpein’ which means ‘to creep’ - appropriate since these viruses cause chronic and recurrent infections. The epidemiology of common herpesvirus infections puzzled doctors for many years. In 1950 it was shown that herpes simplex virus (the virus which causes cold sores and genital herpes) could assume a latent state after an initial infection, becoming reactivated much later. Similarly in 1954 it was shown that varicella zoster virus is the cause of both chicken pox and shingles, diseases which are often separated in the same host by many decades.

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Approximately one hundred different herpesviruses have been isolated, at least one for most animal species which has been examined. To date, there are eight known human herpesviruses.
All the herpesviruses are large and complex viruses with genomes of up to 235 kbp of double-stranded DNA which encode approximately 50 proteins, of which about 35 are found in the virus particle.
The capacity to establish latency is a characteristic feature of all herpesviruses, and involves three separate phases:

• establishment
• maintenance
• reactivation

Following the initial infection, herpesvirus latency occurs within neurons or lymphocytes depending on the virus involved. Establishment and maintenance of latency is complex and not completely understood. During latent infection only a very restricted set of virus genes are expressed and the virus does not actively replicate itself. This state can be maintained for a very long time indeed, often for many decades. At some point, the virus is woken from its slumber, often by a physiological change in the host, or sometimes by an alteration in the status of the immune system.

So clearly, herpesvirus infections are bad? Well yes, unless you want to avoid getting the plague. A paper has just been published in Nature which shows that latent herpesvirus infections alter the host immune system, protecting them from certain bacterial infections (Herpesvirus latency confers symbiotic protection from bacterial infection. 2007 Nature 447: 326-329).
Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically very similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, were shown to be resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. This latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Herpesvirus latency seems to upregulate the basal activation state of the innate immune system.

Our current understanding of cellular and molecular immunity is based largely on studies in pathogen-free mice that have no known herpesvirus infections. This paper demonstrates that herpesvirus infections trigger profound immune modulation, with the potential to alter significantly the kinetics and nature of host responses to pathogens. As there are few herpesvirus-free humans, the authors speculate that a more accurate understanding of ‘normal’ human immunity may require a re-evaluation of immune function in the presence of these symbiotic viruses, which have been exerting selective pressures on the mammalian immune system for millions of years.

Where we used to view the immune evasion capabilities and lifelong persistence of herpesviruses as solely pathogenic, this new data suggests that herpesvirus latency is a symbiotic relationship with immune benefits for the host. It also demonstrates the dangers of a purely molecular reductionist approach to microbiology.

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