Herpesviruses as unrecognised components of the pathogenesis of chronic diseases

A variety of laboratory methods, especially PCR, now make it possible to detect several viruses with extreme sensitivity in blood and body tissues or organs. Inevitably, researchers investigating these viruses have speculated that their detection is associated with the aetiology of the diseases the patients were suffering from. Accordingly, even by limiting the search to herpesviruses, the published literature can be found to contain associations with multiple sclerosis, chronic fatigue syndrome, graft rejection, graft-versus-host disease, and atherosclerosis. Even allowing for the fact that these diseases have complex, multifactorial pathogeneses and that herpesviruses may be making only a partial contribution to disease aetiology or progression, is it plausible that any of these associations may be causal? The lack of essential controls in some of the clinical reports leads sceptical reviewers to reject out of hand all of the reported associations. Indeed, it has been argued in this journal that some viruses should be considered ubiquitous commensals unless proven to be pathogenic by carefully controlled and repeatable experiments [1]. Yet the ubiquitous nature of herpesviruses, their ability to reactivate without always producing symptoms [2], and their ability to modulate immune responses, makes them plausible candidate triggers for exacerbations of complex diseases. Thus, the challenge is to differentiate between causality and epiphenomenology in pathogenesis, so as to prevent both simplistic acceptance of aetiology and denial of true associations. The ®rst approach is to study suf®cient cases and carefully matched controls to demonstrate a statistical association between detection of virus and disease. Case reports of individuals provide no meaningful information in this regard, and should be ignored. Statistically signi®cant association is not proof of causality because some associations may be causal in reverse; e.g. transplant rejection may cause a virus to become detectable because of the effects of immunosuppressive drugs used to treat rejection episodes. Thus, a temporal relationship, where viruses precede or are co-incident with disease, should also be demonstrated. The statistical association should also be replicated by independent investigators. One virus that meets these criteria is the association of HSV with Bell's palsy (reviewed in [3]) now that HSV DNA has been detected in endoneural ̄uid from cases but not controls [4]. Another example concerns the association of CMV with graft rejection, atherosclerosis and fungal septicaemia, known for many years as the ``indirect effects'' of CMV to differentiate them from the ``direct effects'' or end-organ diseases also caused by this virus (reviewed in [5]). A second approach involves cells or animal models to determine if the effects of the virus produce changes consistent with the proposed pathogenesis. Admittedly, it is dif®cult to investigate multiple sclerosis or chronic fatigue syndrome in vitro, but studies of atherosclerosis and graft rejection have demonstrated links with CMV. Thus, in vitro studies show that the CMV gene US28 can increase recruitment of smooth muscle cells to atherosclerotic lesions [6] gene UL122 can block their apoptosis by binding p53 [7], while CMV infection can activate cyclooxygenase 2 to peroxidise lipids [8]. Studies with rat CMV show that this related virus can trigger rejection of cardiac or lung allografts, and that both effects can be blocked by administration of ganciclovir [9]. The third approach is to design double-blind, randomised, placebo-controlled trials of drugs active against the implicated herpesvirus and determine if the disease of interest is reduced. A trial of acyclovir in erythema multiforme showed that this immunopathological recurrent condition could be controlled signi®cantly, so implicating HSV as its major trigger [10]. In contrast, a trial of acyclovir in chronic fatigue syndrome produced no effect [11], while a trial in multiple sclerosis Reviews in Medical Virology Rev. Med. Virol. 2000; 10: 281±283.