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Chapter 16 : Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease

Authors: Edith Acquaye-Seedah1, Zachary P. Frye2, Jennifer A. Maynard3
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Affiliations: 1: Department of Biochemistry, University of Texas at Austin, Austin, TX 78712; 2: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712; 3: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712
Content Type: Monograph
Publication Year: 2015

Category: Clinical Microbiology

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Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, Page 1 of 2

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Abstract:

First visualized in 1904 as large inclusions in tissue sections from luetic infants and isolated in 1957 ( ), the human cytomegalovirus (CMV) is a remarkably successful pathogen. Worldwide, there is a 50 to 90% probability of infection by age 50 without any clear markers of genetic susceptibility. Primary infection results in life-long latency, requiring continuous vigilance by the host immune system and characterized by serum antibody titers and a strong cytotoxic T-cell response. While most individuals will be infected with at least one strain of CMV, infection rarely leads to disease in immunocompetent individuals. However, CMV is a primary cause of congenital neurological defects and causes disease in those with compromised immune systems, such as transplant patients, with only limited therapies available.

Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
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Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease
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Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
/content/10.1128/9781555817411.chap16.fig16-1
Figure 1
Human CMV structure. The 235-kb double-stranded linear DNA genome is surrounded by an icosahedral nucleocapsid, enveloped by the viral tegument proteins (including pp65, which harbors a dominant cytotoxic T lymphocyte epitope) and lipid bilayer, which is studded with at least 20 glycoproteins. The fusogenic glycoprotein gB binds some cell surface receptors and appears to be immunodominant, but neutralizing antibodies recognizing this protein only block viral entry into fibroblasts. The gH/L dimer appears to bind specific receptors and potentiate gB-membrane fusion. When occurring as a gH/L/O complex, it is also involved in entry into fibroblasts, a process that appears to occur via direct membrane fusion. In contrast, the gH/L/UL128-131 pentameric complex is required for entry into epithelial and endothelial cells, a process mediated by endocytosis and low-pH fusion. The gM/N complex is the most abundant on the virion surface, initiating adsorption to cells by binding heparin sulfate proteoglycans. The gN may be heavily glycosylated to shield the virion against antibody recognition.
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10.1128/9781555817411/fig16-1.gif
Image of Figure 1
Figure 1

Human CMV structure. The 235-kb double-stranded linear DNA genome is surrounded by an icosahedral nucleocapsid, enveloped by the viral tegument proteins (including pp65, which harbors a dominant cytotoxic T lymphocyte epitope) and lipid bilayer, which is studded with at least 20 glycoproteins. The fusogenic glycoprotein gB binds some cell surface receptors and appears to be immunodominant, but neutralizing antibodies recognizing this protein only block viral entry into fibroblasts. The gH/L dimer appears to bind specific receptors and potentiate gB-membrane fusion. When occurring as a gH/L/O complex, it is also involved in entry into fibroblasts, a process that appears to occur via direct membrane fusion. In contrast, the gH/L/UL128-131 pentameric complex is required for entry into epithelial and endothelial cells, a process mediated by endocytosis and low-pH fusion. The gM/N complex is the most abundant on the virion surface, initiating adsorption to cells by binding heparin sulfate proteoglycans. The gN may be heavily glycosylated to shield the virion against antibody recognition.

Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
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Figure 2
Human CMV life cycle. (1) The virion binds to cells via the gB and gH/L/UL128-131 glycoproteins and specific cellular receptors, followed by direct membrane fusion (fibroblasts) or endocytosis and low-pH-mediated membrane fusion (endothelial and epithelial cells). (2) The virion contents are released into the cytoplasm, allowing the nucleocapsid to translocate to the nucleus for DNA replication and transcription and packaged viral transcripts to be directly translated. (3) Transcripts are translated in the cytoplasm, followed by processing in the endoplasmic reticulum and Golgi body. (4) Viral DNA and proteins are assembled and enveloped to create new virions, followed by (5) release into the extracellular surroundings or directly into another cell. (6) During this process, fragments of viral proteins are combined with host MHC class I in the endoplasmic reticulum for presentation on the cell surface. Antibodies can directly affect the cellular attachment and internalization steps to prevent primary infection, while T-cell recognition of viral pMHC complexes is crucial for identifying and lysing infected cells.
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Image of Figure 2
Figure 2

Human CMV life cycle. (1) The virion binds to cells via the gB and gH/L/UL128-131 glycoproteins and specific cellular receptors, followed by direct membrane fusion (fibroblasts) or endocytosis and low-pH-mediated membrane fusion (endothelial and epithelial cells). (2) The virion contents are released into the cytoplasm, allowing the nucleocapsid to translocate to the nucleus for DNA replication and transcription and packaged viral transcripts to be directly translated. (3) Transcripts are translated in the cytoplasm, followed by processing in the endoplasmic reticulum and Golgi body. (4) Viral DNA and proteins are assembled and enveloped to create new virions, followed by (5) release into the extracellular surroundings or directly into another cell. (6) During this process, fragments of viral proteins are combined with host MHC class I in the endoplasmic reticulum for presentation on the cell surface. Antibodies can directly affect the cellular attachment and internalization steps to prevent primary infection, while T-cell recognition of viral pMHC complexes is crucial for identifying and lysing infected cells.

Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
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Tables

Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease
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Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
/content/10.1128/9781555817411.chap16.tab16-1
TABLE 1
Treatment spectrum for high-risk CMV demographic groups
Generic image for table
TABLE 1

Treatment spectrum for high-risk CMV demographic groups

Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013
/content/10.1128/9781555817411.chap16.tab16-2
TABLE 2
Antibody-based CMV therapeutics
Generic image for table
TABLE 2

Antibody-based CMV therapeutics

Citation: Acquaye-Seedah E, Frye Z, Maynard J. 2015. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease, p 273-288. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0009-2013

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