scholarly journals Latent infection of myeloid progenitors by human cytomegalovirus protects cells from FAS-mediated apoptosis through the cellular IL-10/PEA-15 pathway

2015 ◽  
Vol 96 (8) ◽  
pp. 2355-2359 ◽  
Author(s):  
Emma Poole ◽  
Jonathan C. H. Lau ◽  
John Sinclair
Keyword(s):  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Myeloid Progenitors

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 Human cytomegalovirus persists in myeloid progenitors and is passed to the myeloid progeny in a latent form

2004 ◽  
Vol 126 (3) ◽  
pp. 410-417 ◽  
Author(s):  
Svetlana F. Khaiboullina ◽  
Jaroslaw P. Maciejewski ◽  
Kirsten Crapnell ◽  
Patricia A. Spallone ◽  
A. Dean Stock ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Latent Form ◽  
Myeloid Progenitors

scholarly journals Interleukin-2 from Adaptive T Cells Enhances Natural Killer Cell Activity against Human Cytomegalovirus-Infected Macrophages

2015 ◽  
Vol 89 (12) ◽  
pp. 6435-6441 ◽  
Author(s):  
Zeguang Wu ◽  
Giada Frascaroli ◽  
Carina Bayer ◽  
Tatjana Schmal ◽  
Thomas Mertens
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Immune Surveillance ◽  
Interleukin 2

ABSTRACTControl of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4+T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV—namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity—but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.IMPORTANCEHuman cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host′s immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4+T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.

scholarly journals Human cytomegalovirus latent infection of granulocyte-macrophage progenitors.

1994 ◽  
Vol 91 (25) ◽  
pp. 11879-11883 ◽  
Author(s):  
K. Kondo ◽  
H. Kaneshima ◽  
E. S. Mocarski
Keyword(s):  
Human Cytomegalovirus ◽  
Latent Infection

scholarly journals Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 937-945 ◽  
Author(s):  
Felicia Goodrum ◽  
Matthew Reeves ◽  
John Sinclair ◽  
Kevin High ◽  
Thomas Shenk
Keyword(s):  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Open Reading Frames ◽  
Progeny Virus ◽  
Recombinant Viruses ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Latently Infected ◽  
Low Passage

AbstractLatency enables human cytomegalovirus (HCMV) to persist in the hematopoietic cells of infected individuals indefinitely and prevents clearance of the pathogen. Despite its critical importance to the viral infectious cycle, viral mechanisms that contribute to latency have not been identified. We compared the ability of low-passage clinical and laboratory-adapted strains of HCMV to establish a latent infection in primary human CD34+ cells. The low-passage strains, Toledo and FIX, established an infection with the hallmarks of latency, whereas the laboratory strains, AD169 and Towne, replicated producing progeny virus. We hypothesized that ULb′ region of the genome, which is unique to low-passage strains, may encode a latency-promoting activity. We created and analyzed recombinant viruses lacking segments or individual open reading frames (ORFs) in the ULb′ region. One 5-kb segment, and more specifically the UL138 ORF, was required for HCMV to establish and/or maintain a latent infection in hematopoietic progenitor cells infected in vitro. This is the first functional demonstration of a virus-coded sequence required for HCMV latency. Importantly, UL138 RNA was expressed in CD34+ cells and monocytes from HCMV-seropositive, healthy individuals. UL138 might be a target for antivirals against latent virus.

scholarly journals Human Cytomegalovirus miR-US33as-5p Targets IFNAR1 to Achieve Immune Evasion During Both Lytic and Latent Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Zhang ◽  
Xin Song ◽  
Ping Ma ◽  
Liping Lv ◽  
Yangyang Zhang ◽  
...  
Keyword(s):  
Viral Load ◽  
Human Cytomegalovirus ◽  
Immune Evasion ◽  
Latent Infection ◽  
Signal Transduction Pathway ◽  
Luciferase Reporter ◽  
Type I ◽  
Immune Evasion Mechanism ◽  
Reporter Assays

As the first line of antiviral defense, type I interferon (IFN) binds IFN receptor 1 (IFNAR1) and IFNAR2 to activate the Jak-STAT signal transduction pathway, producing IFN-stimulated genes (ISGs) to control viral infection. The mechanisms by which human cytomegalovirus (HCMV) counteracts the IFN pathway are only partially defined. We show that miR-US33as-5p encoded by HCMV is expressed in both lytic and latent infection. By analysis with RNA hybrid and screening with luciferase reporter assays, we identified IFNAR1 as a target of hcmv-miR-US33as-5p, which was further verified by examining the expression of two IFNAR1 mutants and the binding of IFNAR1 to miR-US33as-5p/miR-US33as-5p-M1/miR-US33as-5p-M2. We found that after the transfection of miR-US33as-5p mimics into different cell lines, the phosphorylation of downstream proteins and ISG expression were downregulated. Immunofluorescence showed that the miR-US33as-5p mimics also inhibited STAT1 translocation into the nucleus. Furthermore, we constructed HCMV with mutant miR-US33as-5p and determined that the mutation did not affect HCMV replication. We found that MRC-5/human foreskin fibroblast (HFF) cells infected with ΔmiRNA HCMV exhibited higher IFNAR1 and ISG expression and a reduced viral load in the presence of exogenous IFN than cells infected with WT HCMV did, confirming that the knockout of miR-US33as-5p impaired viral resistance to IFN. Finally, we tested the effect of ΔmiRNA HCMV on THP-1 and d-THP-1 cells, common in vitro models of latent infection and reactivation, respectively. Again, we found that cells infected with ΔmiRNA HCMV showed a reduced viral load in the presence of IFN than the control cells did, confirming that miR-US33as-5p also affects IFN resistance during both latency and reactivation. These results indicate a new microRNA (miRNA)-based immune evasion mechanism employed by HCMV to achieve lifelong infection.

Human Cytomegalovirus Infection of Primitive Hematopoietic Progenitor Cells: A Model for Latency.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1703-1703
Author(s):  
Felicia D. Goodrum ◽  
Craig T. Jordan ◽  
Scott S. Terhune ◽  
Kevin P. High ◽  
Thomas Shenk
Keyword(s):  
Bone Marrow ◽  
Viral Replication ◽  
Progenitor Cells ◽  
Human Cytomegalovirus ◽  
In Vitro Model ◽  
Latent Infection ◽  
Cmv Infection ◽  
Aids Patients ◽  
Vitro Model

Abstract Human cytomegalovirus (CMV) is beta-herpesvirus that infects the majority of the population worldwide and establishes a lifelong relationship with its host by way of a latent infection. Although, CMV is of little consequence to healthy individuals, reactivation of CMV from latency can cause life-threatening disease in immunocompromised individuals such as bone marrow transplant recipients and AIDS patients. CMV establishes a latent infection in cells of the hematopoietic system. The focus of our work is to elucidate the mechanisms governing a latent infection and reactivation from latency. It is likely that both viral and cellular mechanisms govern the latent program. We have developed a novel in vitro model for CMV latency using primary human hematopoietic progenitors. Using this model to compare CMV infection in CD34+ hematopoietic subpopulations, the outcome of CMV infection was found to depend on the nature of the subpopulation of cells infected. Only primitive CD34+/CD38− progenitor cells harboured an infection with the hallmarks of latency. This subpopulation transiently expressed a unique subset of CMV genes in the absence of viral replication. Importantly, viral replication could be reactivated from this subpopulation. Other primitive (CD34+/c-kit+) and more mature (CD34+/CD38+ and CD34+/c-kit−) subpopulations resulted in an apparently abortive infection. Strikingly, a CD34+ subpopulation expressing a stem cell phenotype supported a productive infection. These results indicate that cellular determinants contribute to the outcome of HCMV infection in hematopoietic cells. Further, we have also demonstrated that viral determinants play a role in establishing a latent infection using our in vitro model. Comparing the clinical Toledo and FIX strains and the laboratory-adapted AD169 strain of CMV, only the clinical strains were able to establish an infection consistent with latency. AD169, by contrast, replicated productively. Genetic sequences unique to clinical strains have been identified and may contribute to its ability to establish a latent infection in vitro. These studies indicate that both viral and cellular determinants contribute to the establishment of CMV latency. Furthermore, these determinants may serve as targets for CMV disease prophylaxis following bone marrow transplantation or in AIDS patients.

scholarly journals Immunomodulatory Properties of a Viral Homolog of Human Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection

2008 ◽  
Vol 82 (7) ◽  
pp. 3736-3750 ◽  
Author(s):  
C. Jenkins ◽  
W. Garcia ◽  
M. J. Godwin ◽  
J. V. Spencer ◽  
J. Lewis Stern ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Latent Infection ◽  
Cell Types ◽  
Interleukin 10 ◽  
Immune Recognition ◽  
Necrosis Factor Alpha ◽  
Mhc Ii ◽  
Immunosuppressive Cytokine ◽  
The Impact

ABSTRACT Human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic cells, from which it can reactivate to cause significant disease in immunocompromised individuals. HCMV expresses a functional homolog of the immunosuppressive cytokine interleukin-10 (termed cmvIL-10), and alternate splicing of the cmvIL-10 transcript results in expression of a latency-associated cmvIL-10 transcript (LAcmvIL-10). To determine whether LAcmvIL-10 encodes immunosuppressive functions, recombinant LAcmvIL-10 protein was generated, and its impact on major histocompatibility complex class II (MHC-II) expression was examined on granulocyte macrophage progenitor cells (GM-Ps) and monocytes. LAcmvIL-10 (and cmvIL-10) downregulated MHC-II on the surfaces of both cell types. This downregulation was associated with a decrease in total MHC-II protein and transcription of components of the MHC-II biosynthesis pathway. Unlike cmvIL-10, LAcmvIL-10 did not trigger phosphorylation of Stat3, and its ability to downregulate MHC-II was not blocked by neutralizing antibodies to the human IL-10 receptor, suggesting that LAcmvIL-10 either does not engage the cellular IL-10 receptor or utilizes it in a different manner from cmvIL-10. The impact of LAcmvIL-10 on dendritic cell (DC) maturation was also assessed. In contrast to cmvIL-10, LAcmvIL-10 did not inhibit the expression of costimulatory molecules CD40, CD80, and CD86 and the maturation marker CD83 on DCs, nor did it inhibit proinflammatory cytokines (IL-1α, IL-1β, IL-6 and tumor necrosis factor alpha). Thus, LAcmvIL-10 retains some, but not all, of the immunosuppressive functions of cmvIL-10. As GM-Ps and monocytes support latent infection, expression of LAcmvIL-10 may enable HCMV to avoid immune recognition and clearance during latency.

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