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  • 1
    Language: English
    In: Medical microbiology and immunology, December 2016, Vol.205(6), pp.537-547
    Description: Congenital human cytomegalovirus (HCMV) infection is one leading cause of childhood disabilities. Prevention of congenital HCMV disease by vaccination has consequently been identified as a priority public healthcare goal. Several vaccine candidates have been introduced in the past that aimed at the prevention of primary HCMV infection in pregnancy. None of these has provided complete protection, and no licensed vaccine is thus far available. An additional level of complexity has been reached by recent studies indicating that the burden of HCMV transmission and disease following non-primary infections in pregnancy may be higher than previously anticipated. Substantial progress in our understanding of the immunobiology of HCMV infection in pregnancy has fostered studies to test revised or novel vaccine strategies. Preventing HCMV transmission has been identified a surrogate endpoint, rendering the conduction of vaccine studies feasible with reasonable effort. Identification of the glycoprotein complex gH/gL/UL128-131 as a mediator of HCMV host cell tropism and evaluation of that complex as a major target of the neutralizing antibody response made manufacturers consider vaccine candidates that include these proteins. Detailed structural analyses of the neutralizing determinants on HCMV glycoprotein B (gB) have revived interest in using this protein in its pre-fusion conformation for vaccine purposes. Studies in pregnant women and in animal models have provided evidence that addressing the T lymphocyte response by vaccination may be crucial to prevent HCMV transmission to the offspring. CD4 T lymphocytes may be of particular importance in this respect. A simultaneous targeting of both the humoral and cellular immune response against HCMV by vaccination thus appears warranted in order to prevent congenital HCMV infection. There is, however, still need for further research to be able to define an immunological correlate of protection against HCMV transmission during pregnancy. This brief review will highlight recent developments in our understanding of the natural history and immunobiology of HCMV infection in pregnancy and their possible impact on the strategies for the development of an HCMV vaccine.
    Keywords: Congenital Cytomegalovirus Infection ; Cytomegalovirus ; Vaccine ; Cytomegalovirus -- Immunology ; Cytomegalovirus Infections -- Prevention & Control ; Cytomegalovirus Vaccines -- Immunology ; Infectious Disease Transmission, Vertical -- Prevention & Control
    ISSN: 03008584
    E-ISSN: 1432-1831
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  • 2
    Language: English
    In: Medical Microbiology and Immunology, 8/12/2016
    ISSN: 0300-8584
    E-ISSN: 1432-1831
    Source: Springer (via CrossRef)
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(7), p.e103392
    Description: Pandemic and seasonal influenza viruses cause considerable morbidity and mortality in the general human population. Protection from severe disease may result from vaccines that activate antigen-presenting DC for effective stimulation of influenza-specific memory T cells. Special attention is paid to vaccine-induced CD8+ T-cell responses, because they are mainly directed against conserved internal influenza proteins thereby presumably mediating cross-protection against circulating seasonal as well as emerging pandemic virus strains. Our study showed that influenza whole virus vaccines of major seasonal A and B strains activated DC more efficiently than those of pandemic swine-origin H1N1 and pandemic-like avian H5N1 strains. In contrast, influenza split virus vaccines had a low ability to activate DC, regardless which strain was investigated. We also observed that whole virus vaccines stimulated virus-specific CD8+ memory T cells much stronger compared to split virus counterparts, whereas both vaccine formats activated CD4+ Th cell responses similarly. Moreover, our data showed that whole virus vaccine material is delivered into the cytosolic pathway of DC for effective activation of virus-specific CD8+ T cells. We conclude that vaccines against seasonal and pandemic (-like) influenza strains that aim to stimulate cross-reacting CD8+ T cells should include whole virus rather than split virus formulations.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, July 29, 2014, Vol.9(7)
    Description: Pandemic and seasonal influenza viruses cause considerable morbidity and mortality in the general human population. Protection from severe disease may result from vaccines that activate antigen-presenting DC for effective stimulation of influenza-specific memory T cells. Special attention is paid to vaccine-induced CD8.sup.+ T-cell responses, because they are mainly directed against conserved internal influenza proteins thereby presumably mediating cross-protection against circulating seasonal as well as emerging pandemic virus strains. Our study showed that influenza whole virus vaccines of major seasonal A and B strains activated DC more efficiently than those of pandemic swine-origin H1N1 and pandemic-like avian H5N1 strains. In contrast, influenza split virus vaccines had a low ability to activate DC, regardless which strain was investigated. We also observed that whole virus vaccines stimulated virus-specific CD8.sup.+ memory T cells much stronger compared to split virus counterparts, whereas both vaccine formats activated CD4.sup.+ Th cell responses similarly. Moreover, our data showed that whole virus vaccine material is delivered into the cytosolic pathway of DC for effective activation of virus-specific CD8.sup.+ T cells. We conclude that vaccines against seasonal and pandemic (-like) influenza strains that aim to stimulate cross-reacting CD8.sup.+ T cells should include whole virus rather than split virus formulations.
    Keywords: Avian Influenza ; Proteins ; Influenza Vaccines ; T Cells
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: Medical Microbiology and Immunology, 2012, Vol.201(4), pp.567-579
    Description: The phosphoprotein 65 (pp65) of human cytomegalovirus is a prominent target of the antiviral CD8 T lymphocyte response. This study focused on investigating the properties of pp65 that render it a privileged antigen. It was found that pp65 was metabolically stable. The tegument protein was introduced into MHC class I presentation following its delivery via non-replicating dense bodies. No ubiquitination was found on particle-associated pp65. Proof was obtained that pp65 was a nucleocytoplasmic shuttle protein, using heterokaryon analyses. Based on this finding, inhibition experiments showed that presentation of particle-derived pp65 by HLA-A2 was sensitive to the impairment of the CRM1-mediated nuclear export pathway. The data support the idea that particle-derived pp65 can serve as a nuclear reservoir for proteasomal processing and MHC class I presentation, following its CRM1-dependent nuclear export. The presentation of pp65-derived peptides was also impaired by CRM1-inhibition following de novo synthesis of the tegument protein. However, pp65 protein levels were also reduced when blocking CRM1-mediated export after transient expression. This indicated that pp65 expression rather than direct interference with its own nuclear export was responsible for its reduced presentation in this case. The functionality of CRM1-mediated nuclear export is thus important for the presentation of pp65-derived peptides in the context of MHC class I on organ cells, both after exogenous uptake and after de novo synthesis of the tegument protein, but different mechanisms may account for either case.
    Keywords: Cytomegalovirus ; pp65 ; MHC class I ; Nuclear export ; CRM1 ; Nucleocytoplasmic shuttling
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 6
    Language: English
    In: Viruses, 01 January 2014, Vol.6(1), pp.172-188
    Description: Human cytomegalovirus (HCMV) particle morphogenesis in infected cells is an orchestrated process that eventually results in the release of enveloped virions. Proteomic analysis has been employed to reveal the complexity in the protein composition of these extracellular particles. Only limited information is however available regarding the proteome of infected cells preceding the release of HCMV virions. We used quantitative mass spectrometry to address the pattern of viral and cellular proteins in cells, infected with derivatives of the AD169 laboratory strain. Our analyses revealed a remarkable conservation in the patterns of viral and of abundant cellular proteins in cells, infected for 2 hours, 2 days, or 4 days. Most viral proteins increased in abundance as the infection progressed over time. Of the proteins that were reliably detectable by mass spectrometry, only IE1 (pUL123), pTRS1, and pIRS1 were downregulated at 4 days after infection. In addition, little variation of viral proteins in the virions of the different viruses was detectable, independent of the expression of the major tegument protein pp65. Taken together these data suggest that there is little variation in the expression program of viral and cellular proteins in cells infected with related HCMVs, resulting in a conserved pattern of viral proteins ultimately associated with extracellular virions.
    Keywords: Human Cytomegalovirus ; Proteomics ; Mass Spectrometry ; Virions ; Expression Pattern ; Biology
    E-ISSN: 1999-4915
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  • 7
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 June 2014, Vol.192(12), pp.5894-905
    Description: Immunoevasive proteins ("evasins") of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In contrast, recognition of different epitopes presented by the same given MHC I allotype was uniformly reduced. For some allotypes, single evasins largely abolished T cell recognition; for others, a concerted action of evasins was required to abrogate recognition. In infected cells whose Ag presentation efficiency had been enhanced by IFN-γ pretreatment, HCMV evasins cooperatively impared T cell recognition for several different MHC I allotypes. T cell recognition and MHC I surface expression under influence of evasins were only partially congruent, underscoring the necessity to probe HCMV immunomodulation using specific T cells. We conclude that the CD8 T cell evasins of HCMV display MHC I allotype specificity, complementarity, and cooperativity.
    Keywords: Alleles ; Immune Evasion ; Antigens, Viral -- Immunology ; Cd8-Positive T-Lymphocytes -- Immunology ; Cytomegalovirus -- Immunology ; Cytomegalovirus Infections -- Immunology ; Histocompatibility Antigens Class I -- Immunology
    ISSN: 00221767
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    Language: English
    In: Medical microbiology and immunology, June 2015, Vol.204(3), pp.285-93
    Description: The morphogenesis of human cytomegalovirus (HCMV) particles is incompletely understood. Analysis of the protein composition of HCMV virions and subviral dense bodies (DBs) by mass spectrometry provides valuable information to increase our knowledge about viral morphogenesis. Here we addressed the viral proteome of virions and DBs from two fibroblast-passaged isolates and the widely used endotheliotropic TB4-BAC40 strain of HCMV. The results show a striking concordance of the particle proteomes of different strains. One surprising finding was that only low levels of gpUL128-131A were found in TB40-BAC4 virions. These three proteins, together with gH and gL, form a protein complex that is critical for the endothelial cell tropism of that strain. This indicates that either few molecules of that complex per virion or a small fraction of pentamer-positive virions suffice to retain the tropism. Furthermore, using a pp65-deficient variant of TB40-BAC4, we confirm our previous finding that the major tegument protein serves as a scaffold to support the upload of a fraction of the outer tegument proteins into particles. The results demonstrate that HCMV particle morphogenesis is an orchestrated process that leads to the formation of particles with a largely strain-independent protein composition.
    Keywords: Proteome ; Proteomics ; Virion ; Cytomegalovirus -- Classification ; Viral Proteins -- Metabolism
    ISSN: 03008584
    E-ISSN: 1432-1831
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  • 9
    Language: English
    In: Molecular Immunology, June 2012, Vol.51(2), pp.245-253
    Description: ► HCMV US3 attenuates degradation of MHC class I molecules induced by US11. ► Enhanced ER retention of class I molecules is evident during stable co-expression of US3 and US11. ► Co-infection with US3- and US11-expressing viruses results in robust down-regulation of cell surface class I molecules. ► While US3 enhances US2-mediated class I degradation, this viral protein antagonizes the function of the US11 gene product. Human cytomegalovirus (HCMV), a member of the family, is proficient at establishing lifelong persistence within the host in part due to immune modulating genes that limit immune recognition. HCMV encodes at least five glycoproteins within its unique short (US) genomic region that interfere with MHC class I antigen presentation, thus hindering viral clearance by cytotoxic T lymphocytes (CTL). Specifically, US3 retains class I within the endoplasmic reticulum (ER), while US2 and US11 induce class I heavy chain destruction. A cooperative effect on class I down-regulation during stable expression of HCMV US2 and US3 has been established. To address the impact of US3 on US11-mediated MHC class I down-regulation, the fate of class I molecules was examined in US3/US11-expressing cells and virus infection studies. Co-expression of US3 and US11 resulted in a decrease of surface expression of class I molecules. However, the class I molecules in US3/US11 cells were mostly retained in the ER with an attenuated rate of proteasome destruction. Analysis of class I levels from virus-infected cells using HCMV variants either expressing US3 or US11 revealed efficient surface class I down-regulation upon expression of both viral proteins. Cells infected with both US3 and US11 expressing viruses demonstrate enhanced retention of MHC class I complexes within the ER. Collectively, the data suggests a paradigm where HCMV-induced surface class I down-regulation occurs by diverse mechanisms dependent on the expression of specific US genes. These results validate the commitment of HCMV to limiting the surface expression of class I levels during infection.
    Keywords: Antigen Presentation ; Immune Modulation ; Hcmv Us3 and Us11 ; Mhc Class I Molecules ; Proteasome Degradation ; Medicine ; Biology ; Chemistry
    ISSN: 0161-5890
    E-ISSN: 1872-9142
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  • 10
    Language: English
    In: 2013, Vol.9(5), p.e1003383
    Description: Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy. ; Human cytomegalovirus is very widespread. It cannot be eliminated from the body. The health of its host depends on immune responses that are maintained for a lifetime. Virus-specific CD8-positive T cells recognize and kill infected cells before they can produce more virus. Infected cells are recognized because they display MHC class I molecules that have bound a peptide derived from a viral protein. The three most relevant human MHC I genes (HLA-A, -B, -C) occur in many allelic variants that present different viral peptides to different T cells. HCMV encodes several molecules that interfere with stability or localization of HLA class I, but it is unknown how this affects recognition by T cells that recognize infection through different HLA molecules. We show here for one viral antigen, IE-1, that viral interference with T cell recognition strongly depends on the identity of the HLA molecule: HLA-A- and HLA-B-restricted T cells are fully inhibited, but HLA-C-restricted T cells that target an epitope from the same antigen recognize and kill infected cells with high efficiency. Because this population of HLA-C-restricted T cells has superior antiviral function and elevated frequency in the blood, it may be particularly suitable for immunotherapy.
    Keywords: Research Article ; Biology ; Medicine
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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