EDITORIAL Biological synergism between infectiousagents

One does not need a scienti®c or medical degreeto be persuaded that patients infected with twoviruses may have a greater disease burden thanthose infected with only one virus. Yet, one(preferably both) of these quali®cations is essen-tial to understand the myriad ways in whichviruses could interact in the whole humanorganism. By analogy with apo-enzymes andtheir small molecule co-factors, one virus can bedescribed as a co-factor, providing a supplemen-tary role which, while strictly non-essential, maygreatly increase the ef®ciency of the process beingconsidered, be that an enzyme reaction or viralpathogenicity. However, when used to describeinteractions between HIV and other viruses, theterm `co-factor' induces abreaction in someindividuals and has been used loosely by othersin the HIV ®eld when they mean to describe aco-parameter. For this reason, I will use theterm, `biological synergism' to describe co-factorrelationships.

Perhaps surprisingly, there is only one examplein medical virology of one virus providing astructural protein for a second; the hepatitis Bsurface antigen which is an essential component ofthe HDV virion [1]. The probability of a single cellbecoming naturally infected with two viruses maybe just too low to maintain transmission of thedefective partner within a community. If so, thecurrent persistence of HDV can be viewed as a by-product of sociological response to new technol-ogy, i.e. the sharing of hypodermic needles tofacilitate simultaneous co-transmission of twoblood-borne infectious agents. Yet there are otherexamples from cell culture experiments, or fromhumans, of a structural protein from one virussubstituting functionally for another in a non-defective unrelated virion. Thus, vesicular stoma-titis virus can pseudotype in the laboratory withgp120/gp41 of HIV [2], and HSV-2 may pseudo-type in humans with these retroviral glycoproteinsalso [3]. Just as the tropic range of cells infectablewith vesicular stomatitis virus is altered by

pseudotyping, so HSV-2/HIV pseudotypes mayinfect a wider range of cells in vivo [3].

The example of adenovirus facilitating thereplication of a parvovirus (adeno-associatedvirus) further illustrates that the co-operationbetween viruses is not limited to the sharing ofstructural components (reviewed in [4]). Corre-sponding examples in vivo may be severalherpesviruses or HBV whose transactivators cansubstitute for tat and so up-regulate HIV geneexpression [5±7]. This may explain why HHV-6and HIV viral loads are mutually enhanced inorgans co-infected with both viruses [8], and whyHSV-2 and HIV quantities are both high in thelesions of genital herpes in patients co-infectedwith both viruses [9]. Of course, the sharing ofmetabolic pathways may not always be positive;examples of mutual antagonism include com-petition between HIV and HHV-7 for theCD4 receptor [10], and inhibition of HIV entryby blocking of chemokine receptors mediatedby macrophage in¯ammatory proteins encodedwithin the HHV-8 genome [11].

Viruses may also interact in the whole humanby modulating immune responses. Thus, HHV-8and CMV usually cause serious life-threateningdiseases only when the patient is immuno-compromised, as in the case of organ transplanta-tion. A similar context can be provided byextensive infection with HIV, so that the retrovirusallows the full pathological potential of theseherpesviruses to be realised. HIV-inducedimmunosuppression also facilitates the replica-tion of HBV and HCV, allowing these viruses tomove liver failure closer to the top of the list ofconditions which kill AIDS patients now thatHIV itself has been brought under control byhighly active anti-retroviral therapy (HAART).Although HBV and HCV replication is increasedin patients co-infected with HIV, their immuno-suppressed state impairs their ability to mountin¯ammatory responses in the liver which pro-duce the characteristic changes in serum liver

Reviews in Medical Virology Rev. Med. Virol. 2000; 10: 351±353.

Copyright # 2000 John Wiley & Sons, Ltd.

enzymes [12,13]. Thus, increased HBV and HCVreplication may remain hidden from routineclinical observation until extensive liver cirrhosisis established.

Further examples of viral interaction can befound in patients other than those with under-lying HIV infection. Thus, there is some evidencethat active infection with HHV-7 or HHV-6 isassociated with CMV disease, suggesting that partof this clinical problem may be caused by theserelated betaherpesviruses [14±16]. Meanwhile, thepathogenicity of in¯uenza virus can be enhancedby bacterial proteases which cleave the viralhaemagglutinin to its active form [17]. Since fatalin¯uenza is often accompanied by bacterialinfections, it remains possible that this re¯ectsbacterial-viral synergism, as well as secondarybacterial pneumonia, in a respiratory tractdamaged by preceding in¯uenza.

The medical signi®cance of these observations iscomplex and challenging. First, there is a need tounderstand and de®ne the pathological processesinvolved and determine if they truly do operate invivo. Second, they imply that therapeutic inter-ventions may produce clinical bene®ts which defyexplanation unless one is familiar with the conceptof biological synergism. Thus, the survival bene®treported in two double-blind, placebo-controlled,randomised trials of acyclovir [18,19] may repre-sent inhibition of the HSV-mediated up-regulationof HIV. If so, they are the earliest examples ofcombination chemotherapy, pre-dating by half adecade the survival bene®t produced by HAART[20]. Third, they suggest that additional novelinterventions may be possible against the com-bined ravages of the synergistic infectious agents,although such treatment would have been inap-propriate in the past. For example, short-termantibiotic treatment could be tested against pla-cebo as an adjunct to therapy with neuraminidaseinhibitors to determine if inhibition of bacterially-encoded proteases could reduce the severity ofclinical `in¯uenza'. This suggestion illustrates howfar concepts of pathogenesis can be altered byconsidering biological synergism; who wouldhave predicted a decade ago that a virologistcould advocate a controlled trial of antibiotics forthe treatment of proven infection with in¯uenzavirus?

P. D. Grif®ths

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human immunode®ciency virus and hepatitis Cvirus demonstrate higher levels of hepatic HCVRNA. J Viral Hepat 1999; 6(3): 203±208.

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Copyright # 2000 John Wiley & Sons, Ltd. Rev. Med. Virol. 2000; 10: 351±353.