Viral microRNA regulation of Akt is necessary for reactivation of Human Cytomegalovirus from latency in CD34+ hematopoietic progenitor cells and humanized mice.

Human cytomegalovirus (HCMV) actively manipulates cellular signaling pathways to benefit viral replication. Phosphatidyl-inositol 3-kinase (PI3K)/Akt signaling is an important negative regulator of HCMV replication, and during lytic infection the virus utilizes pUL38 to limit Akt phosphorylation and activity. During latency, PI3K/Akt signaling also limits virus replication, but how this is overcome at the time of reactivation is unknown.

Thermal tolerance of cultured and wild Icelandic arctic charr (Salvelinus alpinus) at self-selected flow rates.

Climate change is predicted to change not only the temperature of many freshwater systems but also flow dynamics. Understanding how fishes will fare in the future requires knowing how they will respond to both extended variations of temperature and flow. Arctic charr have had their thermal tolerance measured, but never with respect to flow.

Human cytomegalovirus UL138 interaction with USP1 activates STAT1 in infection.

Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes a life-long latent infection.

Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection.

Unlabelled: Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes a life-long latent infection.

Myeloid cell tropism enables MHC-E-restricted CD8 T cell priming and vaccine efficacy by the RhCMV/SIV vaccine.

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8 T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8 T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component.

Thermal tolerance of cyprinids along an urban-rural gradient: Plasticity, repeatability and effects of swimming and temperature shock.

Urbanization changes the thermal profile of streams in much the same way that climate change is predicted to with higher temperatures, more varied flow and rapid temperature pulses with precipitation events. Whether exceptional tolerance to these altered thermal conditions is a pre-requisite for a fish species to inhabit urban streams or if urbanization has changed the thermal physiology of those fish species that persist in urban streams is unknown, but could help predict the outcome of future climate disruption. To test whether residence in urban streams is associated with altered thermal tolerance, we compared thermal tolerance (CT) and phenotypic plasticity of thermal tolerance (ΔCT/Δ acclimation temperature) in five populations of an urban-tolerant cyprinid, the blacknose dace (Rhinichthys atratulus), from multiple watersheds along an urban/rural gradient.

Human Cytomegalovirus miR-US25-1 Targets the GTPase RhoA To Inhibit CD34 Hematopoietic Progenitor Cell Proliferation To Maintain the Latent Viral Genome.

Human cytomegalovirus (HCMV) microRNAs play essential roles in latency and reactivation in CD34 hematopoietic progenitor cells (HPCs) via regulation of viral and cellular gene expression. In the present study, we show that HCMV miR-US25-1 targets RhoA, a small GTPase required for CD34 HPC self-renewal, proliferation, and hematopoiesis. Expression of miR-US25-1 impairs signaling through the nonmuscle myosin II light chain, which leads to a block in cytokinesis and an inhibition of proliferation.

Cytomegaloviral determinants of CD8 T cell programming and RhCMV/SIV vaccine efficacy.

Simian immunodeficiency virus (SIV) insert-expressing, 68-1 rhesus cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8 T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) have not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions ( and ), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (; ) leads to either of two distinct CD8 T cell response types-MHC-Ia-restricted only or a mix of MHC-II- and MHC-Ia-restricted CD8 T cells.

CD34 Hematopoietic Progenitor Cell Subsets Exhibit Differential Ability To Maintain Human Cytomegalovirus Latency and Persistence.

In human cytomegalovirus (HCMV)-seropositive patients, CD34 hematopoietic progenitor cells (HPCs) provide an important source of latent virus that reactivates following cellular differentiation into tissue macrophages. Multiple groups have used primary CD34 HPCs to investigate mechanisms of viral latency. However, analyses of mechanisms of HCMV latency have been hampered by the genetic variability of CD34 HPCs from different donors, availability of cells, and low frequency of reactivation.

Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways.

Regulation of epidermal growth factor (EGF) receptor (EGFR) signaling is critical for the replication of human cytomegalovirus (HCMV) as well as latency and reactivation in CD34 hematopoietic progenitor cells. HCMV microRNAs (miRNAs) provide a means to modulate the signaling activated by EGF through targeting components of the EGFR signaling pathways. Here, we demonstrate that HCMV miR-US5-2 directly downregulates the critical EGFR adaptor protein GAB1 that mediates activation and sustained signaling through the phosphatidylinositol 3-kinase (PI3K) and MEK/extracellular signal-regulated kinase (ERK) pathways and cellular proliferation in response to EGF.

Human Cytomegalovirus Infection Suppresses CD34 Progenitor Cell Engraftment in Humanized Mice.

Human cytomegalovirus (HCMV) infection is a serious complication in hematopoietic stem cell transplant (HSCT) recipients due to virus-induced myelosuppression and impairment of stem cell engraftment. Despite the clear clinical link between myelosuppression and HCMV infection, little is known about the mechanism(s) by which the virus inhibits normal hematopoiesis because of the strict species specificity and the lack of surrogate animal models. In this study, we developed a novel humanized mouse model system that recapitulates the HCMV-mediated engraftment failure after hematopoietic cell transplantation.

Hypoxia tolerance is unrelated to swimming metabolism of wild, juvenile striped bass ().

Juvenile striped bass residing in Chesapeake Bay are likely to encounter hypoxia that could affect their metabolism and performance. The ecological success of this economically valuable species may depend on their ability to tolerate hypoxia and perform fitness-dependent activities in hypoxic waters. We tested whether there is a link between hypoxia tolerance (HT) and oxygen consumption rate ( ) of juvenile striped bass measured while swimming in normoxic and hypoxic water, and to identify the interindividual variation and repeatability of these measurements.

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34 Hematopoietic Progenitor Cells.

Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT) because of various hematologic problems, including myelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein (NAB1) to induce myelosuppression of uninfected CD34 hematopoietic progenitor cells (HPCs) through an increase in TGF-β production. Infection of HPCs with an HCMVΔmiR-US5-2 mutant resulted in decreased TGF-β expression and restoration of myelopoiesis.

Characterization of a live-attenuated HCMV-based vaccine platform.

Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (T) providing continuous, life-long anti-pathogen immune activity. To allow for the clinical testing of human CMV (HCMV)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone TR3 representing a wildtype genome.

Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency.

Sustained phosphotinositide3-kinase (PI3K) signaling is critical to the maintenance of alpha and beta herpesvirus latency. We have previously shown that the beta-herpesvirus, human cytomegalovirus (CMV), regulates epidermal growth factor receptor (EGFR), upstream of PI3K, to control states of latency and reactivation. How signaling downstream of EGFR is regulated and how this impacts CMV infection and latency is not fully understood.

HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation.

Reactivation of latent Human Cytomegalovirus (HCMV) in CD34+ hematopoietic progenitor cells (HPCs) is closely linked to hematopoiesis. Viral latency requires maintenance of the progenitor cell quiescence, while reactivation initiates following mobilization of HPCs to the periphery and differentiation into CD14+ macrophages. Early growth response gene 1 (EGR-1) is a transcription factor activated by Epidermal growth factor receptor (EGFR) signaling that is essential for the maintenance of CD34+ HPC self-renewal in the bone marrow niche.

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 Hematopoietic Progenitor Cells and Humanized NSG Mice.

Human cytomegalovirus (HCMV) infection of CD34 hematopoietic progenitor cells (CD34 HPCs) provides a critical reservoir of virus in stem cell transplant patients, and viral reactivation remains a significant cause of morbidity and mortality. The HCMV chemokine receptor US28 is implicated in the regulation of viral latency and reactivation. To explore the role of US28 signaling in latency and reactivation, we analyzed protein tyrosine kinase signaling in CD34 HPCs expressing US28.

Repeatability of Hypoxia Tolerance of Individual Juvenile Striped Bass and Effects of Social Status.

Chesapeake Bay is the primary nursery for striped bass (), which are increasingly being exposed to hypoxic waters. Tolerance to hypoxia in fish is generally determined by a single exposure of an isolated individual or by exposing large groups of conspecifics to hypoxia without regard to social status. The importance of social context in determining physiological responses to stressors is being increasingly recognized.

Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation.

The ability of human cytomegalovirus (HCMV) to reactivate from latent infection of hematopoietic progenitor cells (HPCs) is intimately linked to cellular differentiation. HCMV encodes UL7 that our group has shown is secreted from infected cells and induces angiogenesis. In this study, we show that UL7 is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R), a well-known critical factor in HPC differentiation.

Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology.

Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi.

Hypoxia and Sprint Swimming Performance of Juvenile Striped Bass, Morone saxatilis.

Annual hypoxia in the Chesapeake Bay has expanded to the point where Darwinian fitness of juvenile striped bass (Morone saxatilis) may depend on their ability to perform in low-oxygen environments. The locomotion they use in predator/prey dynamics relies primarily on white (type II) muscle that is powered by anaerobic metabolic pathways and has generally been thought to be immune to aquatic hypoxia. We tested the sprint performance of 15 juvenile striped bass twice under acute hypoxia (20% air saturation [AS]) 5 wk apart and once under normoxia (>85% AS) in between.

Modulation of the NFκb Signalling Pathway by Human Cytomegalovirus.

Many viruses trigger innate and adaptive immune responses and must circumvent the negative consequences to successfully establish infection in their hosts. Human Cytomegalovirus (HCMV) is no exception, and devotes a significant portion of its coding capacity to genes involved in immune evasion. Activation of the NFκB signalling pathway by viral binding and entry results in induction of antiviral and pro-inflammatory genes that have significant negative effects on HCMV infection.

Human Cytomegalovirus Induces Cellular and Humoral Virus-specific Immune Responses in Humanized BLT Mice.

The strict species specificity of Human Cytomegalovirus (HCMV) has impeded our understanding of antiviral adaptive immune responses in the context of a human immune system. We have previously shown that HCMV infection of human hematopoietic progenitor cells engrafted in immune deficient mice (huNSG) results in viral latency that can be reactivated following G-CSF treatment. In this study, we characterized the functional human adaptive immune responses in HCMV latently-infected huBLT (humanized Bone marrow-Liver-Thymus) mice.

Correction: Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues.

[This corrects the article DOI: 10.1371/journal.ppat.