EDITORIAL Interactions between viral and human genes

We have previously discussed in these columnsthe phenomenon of ‘‘biological synergism’’ where-by gene products from one virus facilitate thereplication and/or pathogenesis of a second virus[1]. What about similar phenomena resultingfrom interactions between the genes of a virusand those of its host? Contrived experimentswith transgenic mice may provide examples, butdo such interactions occur in the real world ofviruses loose in outbred populations of humans?

Protective cell-mediated immune responses aremounted when peptides derived from viral pro-teins are presented in the context of HLA class Imolecules. Polymorphisms in HLA class I genesmay then be expected to exert differential effectsthrough their affinity for distinct peptides derivedfrom viral proteins. This possibility has been eva-luated directly when comparing the HLA hapolo-types associated with relatively slow progressionof HIV disease and the cellular response of un-infected recipients to immunogenic HIV peptidespresented by recombinant avian poxviruses [2]. Adirect correlation was reported, implying thatfavourable HLA genotypes are explained by theirability to mount protective immune responses.

In contrast, if a potentially fatal virus: immuneinteraction is held in check by an immune res-ponse modulator gene, polymorphism may pre-dispose individuals to severe disease. Thus, theactivity of signalling lymphocyte activation mole-cule (SLAM) is moderated by SLAM associatedprotein (SAP). X-linked lymphoproliferative dis-ease (XLP) results from a mutated SAP gene [3,4].Children born with this genetic change functionnormally until they encounter EBV, illustratingthe specific virus-host interaction essential for dis-ease. In addition, susceptibility to EBV infectionappears to be linked statistically to polymorph-isms in the promoter region of the cellular genefor IL10 [5]. Individuals with the protectivehaplotype have increased spontaneous productionof IL-10, suggesting that this cytokine can protect

against acquisition of EBV [5]. The same muta-tions in the promoter of the host IL-10 are alsoassociated statistically with gastric cancer, some ofwhich have detectable levels of EBV DNA. Com-pared to controls without gastric cancer, themajority form (EBV-negative) was found less fre-quently in those who were high producers ofIL-10 [6]. In contrast, the minority form (EBV-positive) of gastric cancer was significantly asso-ciated with a promoter polymorphism whichproduces high levels of TNF-alpha [6]. Clearlymuch more work will be required to disentanglethe inter-relationships between EBV, TNF-alphaand IL-10 and determine which is important forpathogenesis. However, the results so far are con-sistent with the possibility that the cytokine environ-ment provided by the host may modulate thepathogenic potential of EBV. This concept couldhelp explain how viruses that infect the majorityof the population only affect a minority; why onesuch virus may be associated with more than onedisease, and why particular virus-associated dis-eases are found preferentially in people residingin different parts of the world.

Homozygous individuals who lack a cell sur-face protein used as a viral receptor may be resist-ant to infection. Examples include the globosidereceptor for parvovirus B19 [7] and deletions(such as Delta-32) of the CCR5 gene which actsas a co-receptor for HIV [8]. In the latter case,levels of HIV in the plasma correlate with thedensity of expression on CD4+ T-cells of surfaceCCR5 [9]. This presumably explains why hetero-zygotes can become infected but show delayedprogression of disease, as revealed by studies inadults [10] and in children [11]. Genetic poly-morphisms in CCR5 correlate not only with pro-gression of disease but also with perinataltransmission [12]. The beneficial effect on HIVof heterozygosity for Delta-32 can be counter-balanced by mutations in the gene for stromal-derived factor 1, the natural ligand for CCR5 [13]

Reviews in Medical Virology

Rev. Med. Virol. 2002; 12: 197–199.Published online in Wiley InterScience (www.interscience.wiley.com).

DOI: 10.1002/rmv.364

Copyright # 2002 John Wiley & Sons, Ltd.

or by a disadvantageous haplotype on the otherchromosome [12]. Such compensation for the acti-vity of one mutated gene by another will befamiliar to virologists in the example of changes inhaemagglutinin compensating for mutations inthe neuraminidase of influenza during evolutionof resistance to zanamivir or oseltamivir [14,15].An alternative means of escape from a deleteriousgenetic background includes polymorphisms inthe promoter region of the CCR5 gene itself. Suchchanges remain poorly mapped, but at least one isassociated with increased maternal mortality anda corresponding increase in viral load [16].

It must be remembered that the overall bene-ficial effect of a mutation is modulated by itsprevalence in the community. Thus, the Delta-32genotype is instructive but has a limited effect inone generation because its prevalence is low(y1% homozygosity, 15% heterozygosity) [17].Although Delta-35 mutation is rare in Africans,other changes are found in the gene. Mathematicalmodels show that the CCR5 mutations mostcommon in Africans could lead to an increase inthe average incubation period to AIDS of 2–4years among those perinatally infected with HIV[18]. When compared to an incubation periodshortened by a similar amount in individualslacking these beneficial polymorphisms, this dif-ference represents a major selective pressure forhumans because the average time from infectionto disease is shifted into the major child-bearingyears. Using a time-scale of decades to centuries,extensive relative re-population of African coun-tries with individuals bearing beneficial CCR5mutations should therefore be expected [18]. Thisdramatic change in human genotype is matchedhistorically only by the emergence of heterozy-gous carriers of haemoglobin S, presumed to havebeen selected for during survival against malaria[19]. Thus, where a heritable trait confers a differ-ence in production of offspring, the stage is set forevolution through natural selection. Undoubtedly,more examples of potential viral: host interactionwill emerge from the human genome project but,at this early stage, we should conclude that, notonly do viruses interact with human genes, but atleast one virus is currently driving the evolutionof our species.

P. D. Griffiths

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