Reviews in Medical Virology Rev. Med. Virol. 8: 177–178 (1998)

Puns Aid Understanding ofImmune Evasion Strategies

The immune system sees a bewildering array of epitopesencoded by viruses which can be recognised by B- orT-lymphocytes. Given a catalogue of such responses to asingle virus, how can we differentiate between thosewhich are functionally important and others which aremerely incidental?

One approach is to consider how the virus responds tothe threat of a given set of immune effectors. If a viruswhich has persisted for many generations of humans cancontinue to survive despite our best immune responses,then it may have developed successful strategies to avoidor abrogate them. This is particularly true if the virus caninfect on multiple occasions.

One such virus is HSV, which persists for the life ofthe infected individual, despite prominent T- and B-cellresponses and reactivates from its latent state at periodicintervals to cause disease of the oral or genital mucosa.1

Individuals who are perfectly healthy, with immunesystems that can deal promptly with all other infectiousagents, nevertheless may suffer from frequent HSV recur-rences. However, individuals who are immunocompro-mised have both an increased frequency and severity ofHSV disease, an observation which provided a clue thatT-cell responses are important for the control of HSVinfection.

Viral epitopes are seen by the T-cell immune responsewhen peptides are presented at the plasma membrane ofan infected cell by class I HLA molecules.2 The peptidesare formed by proteolytic cleavage of viral proteins inthe proteosome, a multi-enzyme organelle capable ofdigesting most proteins. They are then transported intothe lumen of the endoplasmic reticulum by the TAPproteins (Transporter associated with Antigen Process-ing) where they assemble with class I heavy chains andâ2-microglobulin to form complexes. These multicompo-nent complexes are transported through the trans-Golgito reach the plasma membrane, where they decorate thesurface of the cell and indicate that non-host proteinsare being synthesised. CTL recognise such complexesand act to destroy the cell by means of one of twodistinct mechanisms, one involving perforin and anothersignalling the cell to commit suicide by means ofFas–ligand interactions.3

How might a virus like HSV interfere with thispathway? HSV has a protein (ICP47) which blocks the

CCC 1052–9276/98/040177–02 $17.50? 1998 John Wiley & Sons, Ltd.

function of TAP proteins so decreasing peptide concen-trations within the endoplasmic reticulum and preventingthe presentation of mature class I complexes in theepithelial cells it infects.4 This simple manoeuvre preventsCTL recognising and killing the HSV-infected cell. Thus,individuals frequently affected by recurrent HSV infectionhave potentially normal CTL responses but a virus whichhas learnt to down-regulate the markers on target cellswhich could allow CTL to act. This explains why patientswith frequently recurring herpes can effectively controlother virus infections. How then is the HSV infectioncurtailed? It transpires that other components of theimmune response become activated leading ultimately toIFNã production and sufficient up-regulation of HLAclass I to allow CTL to terminate the infection.5 Theearliest cells forming an inflammatory infiltratingresponse to HSV lesions are CD4-positive T-cells andmacrophages.6 The IFNã is produced by CD4-positiveT-helper cells activated by macrophages and byLangerhans cells which have processed HSV antigens andsecreted a variety of cytokines including IL-1â, IL-6,IL-12 and the â-chemokine MIP-1â.6,7 IFNã is alsoproduced by activated CTL, thus providing a powerfulpositive feedback.8 Thus, the TAP block is only relativeand interferon-ã production can up-regulate HLA suf-ficiently to terminate the infection so tipping the balancein favour of the immune response. Of course, the HSVmay have transmitted to another individual by then, butthe immune response of the source patient ultimatelygains the upper hand and terminates the bout of activeinfection. This example illustrates the power of themulti-component immune response network, able torespond in several distinct ways to a virus and provide a‘belt and braces’ redundancy through interacting teamefforts. Given this perspective, HSV disease must bemore common in the immunocompromised because, inaddition to the local effects of the virus, such patientshave a relative deficiency of functional CTL.2

What are the puns alluded to in the title? The article4

which described the ICP47 interaction with theTransporter associated with Antigen Processing wasentitled, ‘Herpes simplex virus turns off the TAP to evadehost immunity’. The Commentary5 which recentlydescribed tipping the balance in favour of the host madean allusion to Tip O’Neill, the former speaker of the

178 EDITORIAL

House of Representatives, well known for his aphorism,‘All politics are local’. This parallel between science andpolitics illustrates that understanding what happens at thelocal interface of virus-infected target cells and immunecell interaction may be as important as measuring CTLsin the more readily accessible vascular compartment.

Paul GriffithsJune 1998

REFERENCES

1. Wald, A., Corey, L., Cone, R., Hobson, A., Davis, G.,and Zeh, J. (1997). Frequent genital herpes simplexvirus 2 shedding in immunocompetent women: effectof acyclovir treatment. J. Clin. Invest. 99, 1092–1097.

2. Riddell, S.R. and Greenberg, P.D. (1997). T celltherapy of human CMV and EBV infection inimmunocompromised hosts. Rev. Med. Virol. 7, 181–192.

3. Berke, G. (1995). The CTL’s kiss of death. Cell, 81,9–12.

? 1998 John Wiley & Sons, Ltd.

4. Hill, A., Jugovic, P., York, I., Russ, G., Bennink, J.,Yewdell, J., Ploegh, H., and Johnson, D. (1995). Herpessimplex virus turns off the TAP to evade hostimmunity. Nature 375, 411–415.

5. Posavad, C.M., Koelle, D.M. and Corey, L. (1998).Tipping the scales of herpes simplex virus reacti-vation: the important responses are local. Nat. Med. 4,381–382.

6. Mikloska, Z., Danis, V.A., Adams, S., Lloyd, A.R.,Adrian, D.L. and Cunningham, A.L. (1998). In vivoproduction of cytokines and â (C-C) chemokines inhuman recurrent herpes simplex lesions—Do herpessimplex virus-infected keratinocytes contribute totheir production? J. Infect. Dis. 177, 827–838.

7. Banchereau, J. and Steinman, R.M. (1998). Dendriticcells and the control of immunity. Nature 392, 245–252.

8. Hengel, H., Esslinger, C., Pool, J., Goulmy, E. andKoszinowski, U.H. (1995). Cytokines restore MHCclass I complex formation and control antigen presen-tation in human cytomegalovirus-infected cells. J. Gen.Virol. 76, 2987–2997.

Rev. Med. Virol. 8: 177–178 (1998)