Reviews in Medical Virology Rev. Med. Virol. 9: 73–74 (1999)

Time to Consider the Conceptof a Commensal Virus?

email: paulgrif@rfhsm.ac.uk

For decades, microbiologists have accepted the conceptof a commensal bacterium (literally, ‘one that eats fromthe same table’). The term is typically used to describebacteria that live on the surface of the skin or in the gutlumen, deriving their nutrients from the extracellularphase. Commensal bacteria interact with the host in away termed ‘mutual indifference’, where each aims toignore the other as far as possible, aiming for that nirvanaof host–parasite relationship called symbiosis (literally,‘living together’).

This concept of commensalism has never transferred tothe field of virology.1 Viruses are obligate intracellularparasites, so cells must be actively infected in order toproduce virus particles. It was felt likely that normalcellular function would be perturbed in this processleading inevitably to disease. Indeed, whenever virusescould be cultured, a disease association was usuallyapparent. Even ‘orphan’ viruses found during surveysof apparently well individuals (e.g. ECHO, = entericcytopathogenic human orphan) were eventually reunitedwith their disease ‘parents’.

Notice that active infection with a bacterial or viralpathogen does not guarantee that 100% of individualswill contract disease, e.g. nasal carriage of meningococcileads to frank meningitis in only a small proportion ofpeople, and polioviruses cause disease in only 1% ofinfected cases. Thus, a high disease attack rate is not apre-requisite for classifying an infectious agent as apathogen. Note also that commensals can cause oppor-tunistic disease if the patient is immunocompromised,showing that absolute lack of disease is not a criterion forcommensalism; such agents can still occasionally bite thehand that feeds them at table if the host lowers his or herguard.

We thus have a spectrum ranging from pathogenicbacteria and viruses, opportunistic bacteria and viruses,but commensal bacteria only. Does this classificationrepresent a true phenomenon or might it be an artefact ofthe technology so far available to us, reflecting thepractical difficulty of detecting viruses? There are nowseveral examples in humans showing that, for membersof distinct virus families, the quantity of virus load isrelated to the development of disease.2–5 What if a virus

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existed which did not have the replicative ability to getabove the viral threshold necessary to cause disease?Would this then qualify for the term ’commensal’?Furthermore, now that sensitive molecular biologicaltechniques, particularly polymerase chain reaction andrepresentational difference analysis (RDA) can identifyvanishingly small quantities of viral nucleic acid, mightwe begin to identify commensal viruses?

Possible examples include hepatitis G virus and TTvirus.6,7 These were each identified by investigation ofcases of post-transfusion hepatitis using sensitivemethods, including RDA. For each example, the sub-sequent investigation of cases and controls found nocorrelation between the detection of these viruses and thepresence of chronic hepatitis.8,9 Might they representcommensals which were found simply because they werelooked for? The fact that they may be transmissible byblood would help understand their natural history butwould not prevent their classification as commensals.

If commensal viruses do exist, they would haveimportant implications for the ways in which clinicalresearch is often conducted. The ‘case-report’ is astandard way of describing the progression of a clinicalcondition. When sensitive laboratory techniques are usedto test for the presence of novel viruses, plausibleassociations may be seen which may convince colleaguesthat virus X is the cause of disease Y, despite the caveatsdiscussed in the case report (and often inserted at thebehest of sceptical reviewers). Yet clinical science is notexempt from the mandatory requirement to providecontrols for every observation or experiment and the‘case-report’ may simply have detected a commensalvirus in a disease of unknown aetiology. Current poten-tial candidates10,11 for such coincidental findings includethe association of multiple sclerosis with human herpes-virus 6 and with the presumptiously named ‘MS retro-virus’. A series of cases and matched controls can bestudied but, as discussed recently, it is important toexamine the possibility that immunosuppressive drugssuch as steroids may have activated a virus to its level ofdetectability in cases rather than in controls.12,13 Perhapsthese essential, carefully controlled, clinicopathologicalstudies should be required before a disease-associatedname is given to any novel virus (after all, there are threeclaims to the name ‘hepatitis F’, none of which appears

74 EDITORIAL

substantiated at present; (reviewed in 14). Testing samplesfrom normal healthy individuals rather than from patientsmay reduce the risk of inadvertent disease association,yet may fail to identify true pathogens. For example,Epstein_ Barr virus (EBV) was initially found to infectmost healthy laboratory staff with no apparent diseaseassociation; only when a laboratory technician who was aregular negative control seroconverted to EBV coincidentwith her illness of infectious mononucleosis did apotential true disease become recognised, subsequentlyconfirmed by a population-based study (reviewed in 15).Thus, we need to remember that true viral pathogenshave the potential to cause disease and that differing viralinocula and host environments may facilitate or abrogatethat potential.

It is striking that the potential commensal virusesdiscussed here have been detected in brain or liver, aswell as blood. Since the brain and liver have constitu-tively low levels of HLA class I molecules, these organscould represent reservoirs of persistent infection wherecytotoxic T-lymphocytes have difficulty identifyingvirus-infected cells. If true, this could help explain the lackof inflammatory diseases associated with their presence.Thus, they might persist in a low level replicative phase,being able to exist without inducing disease via virus-induced cytolysis (related to virus load) or virus-inducedimmune destruction cytolysis (which requires virus-encoded peptides to be presented in the context of class1 molecules). Such a scenario is speculative but we shouldnot exclude the possibility that commensal viruses mayexist.

Paul Griffiths

REFERENCES

1. Mims, C., Playfair, J. and Roitt, I. (1998). Thehost–parasite response. In: Medical Microbiology, 2ndedn, ed. by C. Mims, J. Playfair, I. Roitt, pp. 9–20.Mosby, London.

2. Mellors, J. W., Rinaldo, C. R. J., Gupta, P., White, R.M., Todd, J. A. and Kingsley, L. A. (1996). Prognosisin HIV-1 infection predicted by the quantity of virusin plasma. Science 272, 1167–1170.

3. Cope, A. V., Sabin, C., Burroughs, A., Rolles, K.,Griffiths, P. D. and Emery, V. C. (1997). Interrelation-ships among quantity of human cytomegalovirus(HCMV) DNA in blood, donor–recipient serostatus,and administration of methylprednisolone as riskfactors for HCMV disease following livertransplantation. J. Infect Dis. 176, 1484–1490.

Copyright ? 1999 John Wiley & Sons, Ltd.

4. Herz, A.V., Bonhoeffer, S., Anderson, R. M., May, R.M. and Nowak, M. A. (1996). Viral dynamics in vivo:limitations on estimates of intracellular delay andvirus decay. Proc. Natl Acad. Sci. USA 93, 7247–7251.

5. Chayama, K., Tsubota, A., Kobayashi, M. et al.(1997). Pretreatment virus load and multiple aminoacid substitutions in the interferon sensitivity-determining region predict the outcome of interferontreatment in patients with chronic genotype 1bhepatitis C virus infection. Hepatology 25, 745–749.

6. Linnen, J., Wages, J. J., Zhang-Keck, Z. Y., et al.(1996). Molecular cloning and disease association ofhepatitis G virus: a transfusion-transmissible agent.Science 271, 505–508.

7. Nishizawa, T., Okamoto, H., Konishi, K., Yoshizawa,H., Miyakawa, Y. and Mayumi, M. (1997). A novelDNA virus (TTV) associated with elevated trans-aminase levels in posttransfusion hepatitis ofunknown etiology. Biochem. Biophys Res. Commun.241, 92–97.

8. Alter, H. J., Nakatsuji, Y., Melpolder, J., et al. (1997).The incidence of transfusion-associated hepatitis Gvirus infection and its relation to liver disease. N.Engl. J. Med. 336, 747–754.

9. Cossart, Y. (1998). TTV a common virus, butpathogenic? Lancet 352, 164.

10. Challoner, P. B., Smith, K. T., Parker, J. D., et al.(1995). Plaque-associated expression of humanherpesvirus 6 in multiple sclerosis. Proc. Natl Acad.Sci. USA 92, 7440–7444.

11. Perron, H., Garson, J. A., Bedin, F., et al. (1997).Molecular identification of a novel retrovirusrepeatedly isolated from patients with multiplesclerosis. The Collaborative Research Group onMultiple Sclerosis. Proc. Natl Acad. Sci. USA 94,7583–7588.

12. Fillet, A. M., Lozeron, P., Agut, H., Lyon-Caen, O.and Liblau, R. (1998). HHV-6 and multiple sclerosis.Nat. Med 4, 537.

13. Soldan, S. S., Berti, R., Salem, N., et al. (1997).Association of human herpes virus 6 (HHV-6) withmultiple sclerosis: increased IgM response to HHV-6early antigen and detection of serum HHV-6 DNA.Nat. Med. 3, 1394–1397.

14. Harrison, T. J. (1996). New agents of viral hepatitis.Rev. Med. Virol. 6, 61–66.

15. Griffin, B. E. (1998). Relation of Burkitt’s tumor-associated herpes-type virus to infectious mono-nucleosis. (Review of 1967 paper by Henle G, HenleW & Diehl V). Rev. Med. Virol. 8, 61–66.

Rev. Med. Virol. 9: 73–74 (1999)