scholarly journals The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 714
Author(s):  
Luwanika Mlera ◽  
Melissa Moy ◽  
Kristen Maness ◽  
Linh N. Tran ◽  
Felicia D. Goodrum
Keyword(s):  
Human Cytomegalovirus ◽  
Infected Individual ◽  
Viral Latency ◽  
Model Systems ◽  
Host Interactions ◽  
Transplant Patients ◽  
New Findings ◽  
Host Signaling ◽  
Viral Determinants ◽  
Cmv Disease

Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic UL133-UL138 locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients.

scholarly journals Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 444 ◽  
Author(s):  
Donna Collins-McMillen ◽  
Jason Buehler ◽  
Megan Peppenelli ◽  
Felicia Goodrum
Keyword(s):  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Viral Genomes ◽  
Host Interactions ◽  
The Past ◽  
Molecular Determinants ◽  
Host Signaling ◽  
Viral Determinants

Human cytomegalovirus (HCMV) is a beta herpesvirus that establishes a life-long persistence in the host, like all herpesviruses, by way of a latent infection. During latency, viral genomes are maintained in a quieted state. Virus replication can be reactivated from latency in response to changes in cellular signaling caused by stress or differentiation. The past decade has brought great insights into the molecular basis of HCMV latency. Here, we review the complex persistence of HCMV with consideration of latent reservoirs, viral determinants and their host interactions, and host signaling and the control of cellular and viral gene expression that contributes to the establishment of and reactivation from latency.

scholarly journals Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timo W. M. De Groof ◽  
Elizabeth G. Elder ◽  
Eleanor Y. Lim ◽  
Raimond Heukers ◽  
Nick D. Bergkamp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Early Gene ◽  
Latent Reservoir ◽  
Solid Organ ◽  
Cell Transplant ◽  
Viral Receptor ◽  
Transplant Patients ◽  
Latently Infected ◽  
Infected Cells

AbstractLatent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.

scholarly journals Advances in Model Systems for Human Cytomegalovirus Latency and Reactivation

mBio ◽  
2022 ◽  
Author(s):  
Lindsey B. Crawford ◽  
Nicole L. Diggins ◽  
Patrizia Caposio ◽  
Meaghan H. Hancock
Keyword(s):  
Human Cytomegalovirus ◽  
Congenital Abnormalities ◽  
Latent Infection ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Model Systems ◽  
Morbidity And Mortality ◽  
Solid Organ ◽  
Hematopoietic Progenitor ◽  
Myeloid Lineage

Human cytomegalovirus (HCMV) is a highly prevalent beta-herpesvirus and a significant cause of morbidity and mortality following hematopoietic and solid organ transplant, as well as the leading viral cause of congenital abnormalities. A key feature of the pathogenesis of HCMV is the ability of the virus to establish a latent infection in hematopoietic progenitor and myeloid lineage cells.

scholarly journals Efficient Dilution-to-Extinction isolation of novel virus-host model systems for fastidious heterotrophic bacteria

2020 ◽  
Author(s):  
Holger H. Buchholz ◽  
Michelle Michelsen ◽  
Luis M. Bolaños ◽  
Emily Browne ◽  
Michael J. Allen ◽  
...  
Keyword(s):  
Heterotrophic Bacteria ◽  
Nutrient Recycling ◽  
Model Systems ◽  
Metagenomic Data ◽  
Culture Collections ◽  
Genomic Databases ◽  
New Members ◽  
Host Interactions ◽  
Infection Dynamics ◽  
Ecological Patterns

AbstractMicrobes and their associated viruses are key drivers of biogeochemical processes in marine and soil biomes. While viruses of phototrophic cyanobacteria are well-represented in model systems, challenges of isolating marine microbial heterotrophs and their viruses have hampered experimental approaches to quantify the importance of viruses in nutrient recycling. A resurgence in cultivation efforts has improved the availability of fastidious bacteria for hypothesis testing, but this has not been matched by similar efforts to cultivate their associated bacteriophages. Here, we describe a high-throughput method for isolating important virus-host systems for fastidious heterotrophic bacteria that couples advances in culturing of hosts with sequential enrichment and isolation of associated phages. Applied to six monthly samples from the Western English Channel, we first isolated one new member of the globally dominant bacterial SAR11 clade and three new members of the methylotrophic bacterial clade OM43. We used these as bait to isolate 117 new phages including the first known siphophage infecting SAR11, and the first isolated phage for OM43. Genomic analyses of 13 novel viruses revealed representatives of three new viral genera, and infection assays showed that the viruses infecting SAR11 have ecotype-specific host-ranges. Similar to the abundant human-associated phage ΦCrAss001, infection dynamics within the majority of isolates suggested either prevalent lysogeny or chronic infection, despite a lack of associated genes; or host phenotypic bistability with lysis putatively maintained within a susceptible subpopulation. Broader representation of important virus-host systems in culture collections and genomic databases will improve both our understanding of virus-host interactions, and accuracy of computational approaches to evaluate ecological patterns from metagenomic data.

scholarly journals Is HERV-K and HERV-W Expression Regulated by miR-155 in Kidney Transplant Patients with Human Cytomegalovirus Infection?

Intervirology ◽  
2018 ◽  
Vol 61 (1) ◽  
pp. 23-29 ◽  
Author(s):  
Massimiliano Bergallo ◽  
Valentina Daprà ◽  
Cristina Calvi ◽  
Paola Montanari ◽  
Ilaria Galliano ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Human Cytomegalovirus ◽  
Cytomegalovirus Infection ◽  
Transplant Patients ◽  
Kidney Transplant Patients ◽  
Human Cytomegalovirus Infection

scholarly journals A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion- associated CMV infection after marrow transplant [see comments]

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3598-3603 ◽  
Author(s):  
RA Bowden ◽  
SJ Slichter ◽  
M Sayers ◽  
D Weisdorf ◽  
M Cays ◽  
...  
Keyword(s):  
Secondary Analysis ◽  
Marrow Transplant ◽  
Disease Rate ◽  
Blood Products ◽  
Cmv Infection ◽  
Primary Analysis ◽  
Probability Of Survival ◽  
Transplant Patients ◽  
Cmv Disease ◽  
To Receive

We performed a prospective, randomized trial in CMV seronegative marrow recipients to determine if filtered blood products were as effective as CMV-seronegative blood products for the prevention of transfusion- transmitted CMV infection after marrow transplant. Before transplant, 502 patients were randomized to receive either filtered or seronegative blood products. Patients were monitored for the development of CMV infection and tissue-documented CMV disease between days 21 and 100 after transplant. Infections occurring after day 21 from transplant were considered related to the transfusion of study blood products and, thus, were considered evaluable infections for the purpose of this trial. In the primary analysis of evaluable infections, there were no significant differences between the probability of CMV infection (1.3% v 2.4%, P = 1.00) or disease (0% v 2.4%, P = 1.00) between the seronegative and filtered arms, respectively, or probability of survival (P = .6). In a secondary analysis of all infections occurring from day 0 to 100 post-transplant, although the infection rates were similar, the probability of CMV disease in the filtered arm was greater (2.4% v 0% in the seronegative arm, P = .03). However, the disease rate was still within the prestudy clinically defined acceptable rate of < or = 5%. We conclude that filtration is an effective alternative to the use of seronegative blood products for prevention of transfusion- associated CMV infection in marrow transplant patients.

scholarly journals The AP-1 Transcription Factor Is a Key Determinant of Human Cytomegalovirus Latency and Reactivation

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 127
Author(s):  
Benjamin A. Krishna ◽  
Amanda B. Wass ◽  
Christine M. O’Connor
Keyword(s):  
Transcription Factor ◽  
Human Cytomegalovirus ◽  
Infected Individual ◽  
Virus Production ◽  
Mapk Signaling ◽  
Viral Reactivation ◽  
Immediate Early ◽  
Activator Protein 1 ◽  
Latently Infected ◽  
Signaling Axis

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that latently infects hematopoietic progenitor cells (HPCs). Individuals with a competent immune system are, for the most part, asymptomatic for the disease. However when a latently infected individual becomes immunosuppressed, HCMV can reactivate, causing severe morbidity and mortality. While much of the viral genome is transcriptionally silenced during latency, some genes are expressed, including the HCMV-encoded G-protein coupled receptor US28. We showed that US28 expression is required for latency, as it suppressed the activator protein-1 (AP-1) transcription factor by attenuating the AP-1 subunit, fos. In turn, this prevents AP-1 from binding and activating the major immediate early promoter (MIEP), the key promoter regulating the latent-to-lytic transcriptional “switch”. Our new data suggest that US28-mediated signaling during latency attenuates the Src-MAPK signaling axis to regulate AP-1. We find that US28 expression suppresses Src, MEK, and ERK, as well as fos phosphorylation and AP-1 binding to the MIEP. Conversely, the pharmacological inhibition of Src, MEK, or ERK in US28Δ-latently infected HPCs suppresses infectious virus production, demonstrating the important role for this signaling axis during latency. Our recent data also reveal that regulating AP-1 is a key determinant in balancing HCMV latency and reactivation. Infection with a virus in which we disrupted the proximal AP-1 binding site in the MIEP (AP-1Δp) leads to reduced AP-1 binding and inefficient viral reactivation compared to wild type. Furthermore, AP-1 is critical for the de-repression of MIEP-driven transcripts and downstream early and late genes, while other immediate early genes remain unaffected. Collectively, these data suggest that AP-1 binding to the MIEP is suppressed during latency, but is required for the efficient transactivation of the MIEP during reactivation. We are currently elucidating US28’s involvement in recruiting AP-1 to the MIEP during reactivation.

scholarly journals The Status of Vaccine Development Against the Human Cytomegalovirus

2020 ◽  
Vol 221 (Supplement_1) ◽  
pp. S113-S122 ◽  
Author(s):  
Stanley A Plotkin ◽  
Dai Wang ◽  
Abdel Oualim ◽  
Don J Diamond ◽  
Camille N Kotton ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Vaccine Development ◽  
National Institutes Of Health ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Stage Of Development ◽  
The Status ◽  
Cmv Disease ◽  
Transplanted Organs ◽  
Congenital Cmv

Abstract Numerous candidate vaccines against cytomegalovirus (CMV) infection and disease are in development. Whereas the previous article [1] provides background and opinions about the issues relating to vaccination, this article provides specifics about the vaccines in active development, as reported at a National Institutes of Health-sponsored meeting in Bethesda on September 4–6, 2018. Here, vaccine developers provide synopses of their candidate vaccines to immunize women to protect against congenital CMV disease and to prevent the consequences of CMV disease in recipients of transplanted organs or hematopoietic stem calls. The projects are presented here roughly in the descending order of their stage of development in the opinion of the first author.

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