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Chapter 22 : Cytomegalovirus

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Abstract:

Human cytomegalovirus (HCMV) was first isolated 50 years ago, when the new technology of cell culture became available. The pathogenesis of HCMV disease is complex, involving contributions from the host as well as from the virus. Increasing knowledge about the genetic composition of the virus can help to illuminate this complex series of relationships and provide a rational basis for therapeutic intervention and prevention of disease. The major immediate-early promoter (MIEP) enhancer contains multiple recognition sites for the transcription factors. Additionally, the MIEP is specifically transactivated by the tegument protein pp71, which is released as soon as incoming virions are uncoated. Thus, HCMV employs multiple methods independent of de novo viral gene expression to induce an intracellular milieu favorable to the initiation of immediate-early (IE) gene transcription. Humoral immunity could reduce the level of HCMV replication and reduce disease without being able to eliminate infection entirely. Humoral immune responses are directed against multiple CMV proteins, including surface glycoproteins, phosphoproteins of the tegument, and structural proteins of the capsid. Reverse transcription-PCR (RT-PCR) should detect only cells in which HCMV is replicating, since the target is mRNA. A nucleic acid sequence-based amplification NASBA assay for the detection of a late gene transcript (pp67) appears to be sensitive and specific and is available commercially.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22

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Image of FIGURE 1
FIGURE 1

Schematic representation of epitopes identified on gpUL55 (gB) and gpUL75 (gH). Numbers represent codons.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 2
FIGURE 2

The major IE region of HCMV showing the splicing events that produce distinct proteins. TA, transcriptional activation; PA, polyadenylation; l.mRNA, late mRNA.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 3
FIGURE 3

Regulation of the major IE region of HCMV. CRS, repression sequence.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 4
FIGURE 4

Effect of HCMV proteins on display of mature HLA complexes at the plasma membrane (PM). TAP, transporter associated with antigen presentation; RIB, ribosome; PRO, proteasome. The empty oval represents unknown binding factor.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 5
FIGURE 5

Age-specific prevalence of IgG antibodies against HCMV.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 6
FIGURE 6

CMV load in the urine of neonates. TCID, 50% tissue culture infective dose. Symbols: ○, symptomatic congenital infection; ●, asymptomatic; ■, natal infection. Error bars indicate standard errors of the means.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 7
FIGURE 7

CMV load in the urine of renal transplant recipients.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 8
FIGURE 8

Threshold concept of CMV pathogenesis.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 9
FIGURE 9

Histologic section of a lung sample from a patient with HCMV pneumonitis following bone marrow transplantation. Arrows show alveolar macrophages bearing the typical intranuclear inclusions of HCMV. An interstitial mononuclear cell infiltrate is seen. (Courtesy of J. E. McLoughlin [from a patient under the care of H. G. Prentice, Royal Free and University College Medical School].)

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 10
FIGURE 10

Histologic appearance of the inner ear in a patient with a fatal case of cytomegalic inclusion disease. Note the focus of large inclusion-bearing cells and accompanying inflammation. (Courtesy of S. Stagno. Reprinted from reference with permission.)

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 11
FIGURE 11

Correlation between high HCMV load and detection of intranuclear inclusions. ge, genomes.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 12
FIGURE 12

Photograph of human embryonic lung fibroblasts showing the focal CPE of HCMV. (Figure prepared by J. A. Bishop.)

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 13
FIGURE 13

Herd immunity for HCMV or rubella. _____, -CMV study 1; ...., CMV study 2; ----, rubella.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 14
FIGURE 14

Standard population models of susceptible, infectious, and immune individuals, modified to include seropositive individuals who act as a source of HCMV for reinfections.

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Image of FIGURE 15
FIGURE 15

Schematic representation of the UL97 gene showing mutations at particular codons that have been proven to cause resistance to ganciclovir in vivo or which are associated with maribavir resistance in vitro. Bold letters indicate mutations confirmed by site-directed mutagenesis. Mutations 460 to 607 concern ganciclovir; mutations 353 to 411 concern maribavir. (Data from reference .)

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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Tables

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TABLE 1

HCMV envelope glycoproteins

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 2

Eleven loci required for HCMV replication

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 3

HCMV immune evasion genes

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
Generic image for table
TABLE 4

Site of HCMV detection by cell culture in 47 AIDS patient autopsies

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
Generic image for table
TABLE 5

Comparison of PCR and culture for 150 immunocompromised patients

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
Generic image for table
TABLE 6

Univariate and multivariate assessment of prognostic factors for HCMV disease in renal allograft recipients

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
Generic image for table
TABLE 7

HCMV diseases in immunocompromised persons

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 8

Clinical features of cytomegalic inclusion disease

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 9

Disease outcome in 1,000 babies born with congenital HCMV infection

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 10

HCMV detection in body fluids

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 11

Misleading concepts about HCMV derived from propagation of the virus in fibroblast cultures

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 12

Vaccine candidates studied clinically

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 13

Populations in whom efficacy of HCMV vaccines could be evaluated by using virologic endpoints

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 14

Strategies for chemotherapy of HCMV

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22
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TABLE 15

Double-blind, placebo-controlled, randomized trials for HCMV

Citation: Griffiths P, Clive Emery V, Milne R. 2009. Cytomegalovirus, p 475-506. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch22

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