Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

Böhm, Verena; Seckert, Christof K.; Simon, Christian O.; Thomas, Doris; Renzaho, Angélique; Gendig, Dorothea; Holtappels, Rafaela; Reddehase, Matthias J.

doi:10.1128/jvi.01143-09

Cited by 19 publications

(9 citation statements)

References 46 publications

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“…Importantly, partial inflation has been demonstrated in very young CMV-infected humans, whose CMV-specific CD8 T-cells develop T EM phenotypes but are not as inflated as elderly hosts [50], as well as adults whose responses (despite absolute magnitude) seem to be mostly T EM . Our findings are also consistent with murine work by others, including Andrews et al who showed the influence of viral load on magnitude of very early CD-8 T-memory responses in BALB mice [25], Bohm et al who showed correlation between tissue viral load and CD8 inflation in BALB mice [26], and finally work from Snyder et al who have shown similar dose dependent impacts on CD8 memory inflation in C57BL6 mice [15]. …”

Section: Discussionsupporting

confidence: 92%

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Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

et al. 2016

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Cytomegalovirus (CMV) has been shown to induce large populations of CD8 T-effector memory cells that unlike central memory persist in large quantities following infection, a phenomenon commonly termed “memory inflation”. Although murine models to date have shown very large and persistent CMV-specific T-cell expansions following infection, there is considerable variability in CMV-specific T-memory responses in humans. Historically such memory inflation in humans has been assumed a consequence of reactivation events during the life of the host. Because basic information about CMV infection/re-infection and reactivation in immune competent humans is not available, we used a murine model to test how primary infection, reinfection, and reactivation stimuli influence memory inflation. We show that low titer infections induce “partial” memory inflation of both mCMV specific CD8 T-cells and antibody. We show further that reinfection with different strains can boost partial memory inflation. Finally, we show preliminary results suggesting that a single strong reactivation stimulus does not stimulate memory inflation. Altogether, our results suggest that while high titer primary infections can induce memory inflation, reinfections during the life of a host may be more important than previously appreciated.

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Section: Discussionsupporting

confidence: 92%

“…Recent work by Reddehase et al has suggested that CD8 memory inflation after mCMV infection might be directly related to viral load [26]. If this is true, then based upon our T-cell results, we would expect to see significantly lower viral loads in mice infected with lower titers.…”

Section: Resultssupporting

confidence: 48%

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

et al. 2016

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“…What clearly supports this hypothesis is the murine model of CMV latency and reactivation postulated by Reddehase and his collegues (36,37). This model proposes that mouse CMV reactivation may occur independently for each latently infected cell and may be putatively defined by a random pattern of silenced and desilenced genes (1,21,42). Consequently, reactivation from latency can be regarded as a stochastic process, and the number of latent genomes cannot be estimated by analysis at a single time point.…”

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confidence: 89%

Deep Sequencing Reveals Highly Complex Dynamics of Human Cytomegalovirus Genotypes in Transplant Patients over Time

Görzer

Godballe

Trajanoski

et al. 2010

J Virol

111

105

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In lung transplant patients undergoing immunosuppression, more than one human cytomegalovirus (HCMV) genotype may emerge during follow-up, and this could be critical for the outcome of HCMV infection. Up to now, many cases of infection with multiple HCMV genotypes were probably overlooked due to the limitations of the current genotyping approaches. We have now analyzed mixed-genotype infections in 17 clinical samples from 9 lung transplant patients using the highly sensitive ultradeep-pyrosequencing (UDPS) technology. UDPS genotyping was performed at three variable HCMV genes, coding for glycoprotein N (gN), glycoprotein O (gO), and UL139. Simultaneous analysis of a mean of 10,430 sequence reads per amplicon allowed the relative amounts of distinct genotypes in the samples to be determined down to 0.1% to 1% abundance. Complex mixtures of up to six different HCMV genotypes per sample were observed. In all samples, no more than two major genotypes accounted for at least 88% of the HCMV DNA load, and these were often accompanied by up to four low-abundance genotypes at frequencies of 0.1% to 8.6%. No evidence for the emergence of new genotypes or sequence changes over time was observed. However, analysis of different samples withdrawn from the same patients at different time points revealed that the relative levels of replication of the individual HCMV genotypes changed within a mixed-genotype population upon reemergence of the virus. Our data show for the first time that, similar to what has been hypothesized for the murine model, HCMV reactivation in humans seems to occur stochastically.Human cytomegalovirus (HCMV) is the most important viral pathogen affecting patients after solid organ transplantation (12,18,29). Lung transplant recipients have an especially high risk of acquiring severe and sometimes fatal HCMV infections, which are also associated directly or indirectly with graft rejection and bronchiolitis obliterans syndrome (6, 53).Human cytomegalovirus is a double-stranded DNA virus with a genome size of about 236 kb that is predicted to contain 165 protein-coding genes (9). Although most of the HCMV genome is highly conserved among the various HCMV strains, a subset of genes exhibits a high degree of variability, as has been shown by genome-wide sequence analysis as well as by examination of individual genes. A high level of genetic heterogeneity usually occurs in a limited number of distinct genotypes (9, 32, 33). Among the most variable genes are the viral envelope glycoprotein N (gN) and gO genes and the gene encoding the predicted membrane glycoprotein UL139. Sequence analysis of highly polymorphic regions within these three genes allows the discrimination of seven distinct gN genotypes (30, 31) and eight distinct gO and UL139 genotypes (3,24,35,45). The existence of such a large number of distinct genotypes provides a useful tool for investigating HCMV population diversity within a host.Reinfection with different HCMV strains is possible in the human host, and several strains can accumulate during...

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“…In the MCMV model, evasins interfere with antiviral protection through certain virus-specific T cells (62,63) and enhance viral latency (64), in the face of a paradoxically increased T cell response that is likely due to more efficient cross-presentation of viral Ag (65). In a rhesus macaque model, deletion of US2-11 does not alter the course of primary CMV infection but prevents superinfection of CMV-positive animals (66).…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Ameres

Besold

Plachter

et al. 2014

The Journal of Immunology

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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.

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Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

Cited by 19 publications

References 46 publications

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

Deep Sequencing Reveals Highly Complex Dynamics of Human Cytomegalovirus Genotypes in Transplant Patients over Time

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

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