Cytomegaloviruses: their drive to achieve permanent coexistence with their hosts

Abstract

Cytomegaloviruses (CMVs) are a fascinating group of herpesviruses that persist for the life of the host in the face of a primed immune system, apparently within the most immune-exposed tissue of all—professional antigen-presenting cells[1xSoderberg-Naucler, C. et al. Cell. 1997; 91: 119–126Abstract | Full Text | Full Text PDF | PubMed | Scopus (438)See all References][1]. The CMVs encode a variety of genes whose function is to subvert the immune response. These include inhibitors of natural killer cell function, chemokine and cytokine homologues and receptor homologues, and several genes involved in subversion of the major histocompatibility complex (MHC) class I-restricted pathway of antigen presentation.The recent Trends Microbiol. review of immune evasion by CMV by Hartmut Hengel, Wolfram Brune and Ulrich Koszinowski[2xHengel, H., Brune, W., and Koszinowski, U.H. Trends Microbiol. 1998; 6: 190–197Abstract | Full Text | Full Text PDF | PubMed | Scopus (164)See all References][2]comprises a detailed catalogue of the CMV genes so far known to be involved in immune avoidance. This is combined with a bird's-eye view of the host-virus relationship, summarized by the authors as the virus' drive `to achieve permanent coexistence with their hosts'. The ability to move comfortably between these two perspectives reflects the length and depth of the involvement of this research group in the study of CMV immunobiology; this welcome review succinctly summarizes their view of this most complicated subject.One of the main impressions on reading the Hengel et al. review is of the discrepancy between the increasingly sophisticated understanding of the molecular mechanisms of CMV immune evasion, particularly the inhibition of the MHC class I pathway of antigen processing, and any firm knowledge of how these mechanisms contribute to the viruses achieving permanent coexistence with their hosts in vivo. It has seemed obvious to some authors that any immune avoidance is advantageous to the virus, but permanent coexistence requires the continued wellbeing of the host while maintaining the ability of the virus to replicate itself sufficiently to infect naive hosts—seemingly contradictory tasks. We are given a clue to the complexity of this task by the very number of immune-avoidance genes. For instance, human CMV (HCMV) has four genes that target MHC class I, and yet cytotoxic T lymphocytes (CTLs) that recognize class I are critical for control of HCMV infection. But what is also difficult to understand is how these immune-evasion techniques can prevent CTL eradication of the virus from professional antigen-presenting cells of the macrophage/dendritic lineage while allowing complete immune control of the virus in poor antigen-presenting cells, such as hepatocytes and lung epithelia.Such questions will probably have to be answered in the murine CMV (MCMV)model, and it is likely that several approaches will be needed. First, viruses lacking immune-evasion genes, either alone or in combination, can be studied in vivo. The development of a bacterial artificial chromosome system for genetic manipulation of herpesvirus genomes by Koszinowski's group[3xMesserle, M. et al. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 14759–14763Crossref | PubMed | Scopus (285)See all References][3]will greatly facilitate these studies, and the first reports of in vivo studies are eagerly awaited. Second, I believe that much will be learned from in vitro studies with mutants infecting biologically relevant cell types, including cells of the macrophage/dendritic lineage. For this reason, the unpublished data of Hengel referred to in the Trends Microbiol. review[2xHengel, H., Brune, W., and Koszinowski, U.H. Trends Microbiol. 1998; 6: 190–197Abstract | Full Text | Full Text PDF | PubMed | Scopus (164)See all References][2]—suggesting that these cells are `resistant to the subversive effects of CMVs on class I'—are particularly interesting. It will be important to determine whether the mechanism of this resistance is quantitative (i.e. resulting from the highly efficient antigen-processing pathways of these cells), as the authors suggest, or qualitative. Either way, if these cells are efficient at presenting CMV antigens to CTLs, how is latency achieved in this cell population? Again, publication of these data is eagerly awaited. Finally, I suspect that we need a more quantitative approach to assessing the efficacy of antigen presentation in the presence of these functions. It may even be necessary to resort to the sorts of mathematical models that best explain the complicated balance between that other persistent virus, HIV, and its beleaguered host immune system[4xNowak, M. and Bangham, C. Science. 1996; 272: 74–79Crossref | PubMedSee all References][4].