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Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease

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  • Authors: Edith A. Seedah1, Zachary P. Frye2, Jennifer A. Maynard3
  • Editors: James E. Crowe Jr.4, Diana Boraschi5, Rino Rappuoli6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    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; 4: Vanderbilt University School of Medicine, Nashville, TN; 5: National Research Council, Pisa, Italy; 6: Novartis Vaccines, Siena, Italy
  • Source: microbiolspec January 2014 vol. 2 no. 1 doi:10.1128/microbiolspec.AID-0009-13
  • Received 05 May 2013 Accepted 08 May 2013 Published 29 January 2014
  • Correspondence: Jennifer A. Maynard, maynard@che.utexas.edu
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  • Abstract:

    Human cytomegalovirus (CMV) is the major cause of congenital neurological defects in the United States and also causes significant morbidity and mortality for hematopoietic and solid organ transplant patients. Primary infection in immunocompetent individuals rarely causes disease but resolves as a life-long latent infection, characterized by sustained antibody and cellular responses. Despite considerable efforts over the last 40 years to develop live attenuated and subunit vaccines, none is close to receiving regulatory approval. However, there is evidence that antibodies can prevent primary infection and cytotoxic T cells can suppress secondary infection. Prior maternal infection decreases the risk a fetus will contract CMV, while adoptive transfer of virus-specific CD8 T cells is highly protective against CMV disease in hematopoietic stem cell transplant recipients. As a result, three polyclonal immunoglobulin preparations are approved for clinical use and one monoclonal antibody has reached phase III trials. Enhanced understanding of the viral life cycle from a biochemical perspective has revealed additional targets for neutralizing antibodies in the gH/gL/UL128-131 pentamer. Until an effective vaccine is licensed, passive immunotherapeutics may present an alternative to maintain viral loads and prevent CMV disease in susceptible populations. This review summarizes the progress and potential of immunotherapeutics to treat CMV infection.

  • Citation: Seedah E, Frye Z, Maynard J. 2014. Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease. Microbiol Spectrum 2(1):AID-0009-13. doi:10.1128/microbiolspec.AID-0009-13.

Key Concept Ranking

Major Histocompatibility Complex
0.44824827
Immune Systems
0.44071224
Viral Life Cycle
0.40430012
0.44824827

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/content/journal/microbiolspec/10.1128/microbiolspec.AID-0009-13
2014-01-29
2017-09-20

Abstract:

Human cytomegalovirus (CMV) is the major cause of congenital neurological defects in the United States and also causes significant morbidity and mortality for hematopoietic and solid organ transplant patients. Primary infection in immunocompetent individuals rarely causes disease but resolves as a life-long latent infection, characterized by sustained antibody and cellular responses. Despite considerable efforts over the last 40 years to develop live attenuated and subunit vaccines, none is close to receiving regulatory approval. However, there is evidence that antibodies can prevent primary infection and cytotoxic T cells can suppress secondary infection. Prior maternal infection decreases the risk a fetus will contract CMV, while adoptive transfer of virus-specific CD8 T cells is highly protective against CMV disease in hematopoietic stem cell transplant recipients. As a result, three polyclonal immunoglobulin preparations are approved for clinical use and one monoclonal antibody has reached phase III trials. Enhanced understanding of the viral life cycle from a biochemical perspective has revealed additional targets for neutralizing antibodies in the gH/gL/UL128-131 pentamer. Until an effective vaccine is licensed, passive immunotherapeutics may present an alternative to maintain viral loads and prevent CMV disease in susceptible populations. This review summarizes the progress and potential of immunotherapeutics to treat CMV infection.

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Figures

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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. doi:10.1128/microbiolspec.AID-0009-2013.f1

Source: microbiolspec January 2014 vol. 2 no. 1 doi:10.1128/microbiolspec.AID-0009-13
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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. doi:10.1128/microbiolspec.AID-0009-2013.f2

Source: microbiolspec January 2014 vol. 2 no. 1 doi:10.1128/microbiolspec.AID-0009-13
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Tables

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TABLE 1

Treatment spectrum for high-risk CMV demographic groups

Source: microbiolspec January 2014 vol. 2 no. 1 doi:10.1128/microbiolspec.AID-0009-13
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TABLE 2

Antibody-based CMV therapeutics

Source: microbiolspec January 2014 vol. 2 no. 1 doi:10.1128/microbiolspec.AID-0009-13

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