scholarly journals PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Viruses ◽  
2015 ◽  
Vol 8 (1) ◽  
pp. 7 ◽  
Author(s):  
Amanda Panfil ◽  
Jacob Al-Saleem ◽  
Cory Howard ◽  
Jessica Mates ◽  
Jesse Kwiek ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Infected Cell ◽  
Cell Survival ◽  
Cell Transformation ◽  
Viral Gene Expression ◽  
Selective Inhibition ◽  
Viral Gene

scholarly journals Latency Reversing Agents: Kick and Kill of HTLV-1?

2021 ◽  
Vol 22 (11) ◽  
pp. 5545
Author(s):  
Annika P. Schnell ◽  
Stephan Kohrt ◽  
Andrea K. Thoma-Kress
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Viral Gene Expression ◽  
Cytotoxic T Cell ◽  
Viral Gene ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Reversing Agents ◽  
Ctl Responses

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.

scholarly journals HCMV Infection and Apoptosis: How Do Monocytes Survive HCMV Infection?

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 533 ◽  
Author(s):  
Donna Collins-McMillen ◽  
Liudmila Chesnokova ◽  
Byeong-Jae Lee ◽  
Heather Fulkerson ◽  
Reynell Brooks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Survival ◽  
Hcmv Infection ◽  
Viral Gene Expression ◽  
Multiple Organ ◽  
Viral Gene ◽  
Blood Monocytes ◽  
Induced Differentiation ◽  
Organ Systems

Human cytomegalovirus (HCMV) infection of peripheral blood monocytes plays a key role in the hematogenous dissemination of the virus to multiple organ systems following primary infection or reactivation of latent virus in the bone marrow. Monocytes have a short life span of 1–3 days in circulation; thus, HCMV must alter their survival and differentiation to utilize these cells and their differentiated counterparts—macrophages—for dissemination and long term viral persistence. Because monocytes are not initially permissive for viral gene expression and replication, HCMV must control host-derived factors early during infection to prevent apoptosis or programmed cell death prior to viral induced differentiation into naturally long-lived macrophages. This review provides a short overview of HCMV infection of monocytes and describes how HCMV has evolved to utilize host cell anti-apoptotic pathways to allow infected monocytes to bridge the 48–72 h viability gate so that differentiation into a long term stable mature cell can occur. Because viral gene expression is delayed in monocytes following initial infection and only occurs (begins around two to three weeks post infection in our model) following what appears to be complete differentiation into mature macrophages or dendritic cells, or both; virally-encoded anti-apoptotic gene products cannot initially control long term infected cell survival. Anti-apoptotic viral genes are discussed in the second section of this review and we argue they would play an important role in long term macrophage or dendritic cell survival following infection-induced differentiation.

Differential viral gene expression and its effect on the biological properties of the cell clones of an HIV-1-infected cell line

Virology ◽  
1990 ◽  
Vol 177 (1) ◽  
pp. 380-383 ◽  
Author(s):  
V.S. Kalyanaraman ◽  
V. Rodriguez ◽  
S. Josephs ◽  
R.C. Gallo ◽  
M.G. Sarngadharan
Keyword(s):  
Gene Expression ◽  
Infected Cell ◽  
Cell Line ◽  
Viral Gene Expression ◽  
Biological Properties ◽  
Viral Gene ◽  
Infected Cell Line ◽  
Cell Clones ◽  
Hiv 1

scholarly journals The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation

2008 ◽  
Vol 82 (23) ◽  
pp. 11637-11650 ◽  
Author(s):  
Verena Böhm ◽  
Christian O. Simon ◽  
Jürgen Podlech ◽  
Christof K. Seckert ◽  
Dorothea Gendig ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Negative Feedback ◽  
Cd8 T Cells ◽  
Viral Gene Expression ◽  
Cd8 T Cell ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Infected Cells

ABSTRACT Cytomegaloviruses express glycoproteins that interfere with antigen presentation to CD8 T cells. Although the molecular modes of action of these “immunoevasins” differ between cytomegalovirus species, the convergent biological outcome is an inhibition of the recognition of infected cells. In murine cytomegalovirus, m152/gp40 retains peptide-loaded major histocompatibility complex class I molecules in a cis-Golgi compartment, m06/gp48 mediates their vesicular sorting for lysosomal degradation, and m04/gp34, although not an immunoevasin in its own right, appears to assist in the concerted action of all three molecules. Using the Ld-restricted IE1 epitope YPHFMPTNL in the BALB/c mouse model as a paradigm, we provide here an explanation for the paradox that immunoevasins enhance CD8 T-cell priming although they inhibit peptide presentation in infected cells. Adaptive immune responses are initiated in the regional lymph node (RLN) draining the site of pathogen exposure. In particular for antigens that are not virion components, the magnitude of viral gene expression providing the antigens is likely a critical parameter in priming efficacy. We have therefore focused on the events in the RLN and have related priming to intranodal viral gene expression. We show that immunoevasins enhance priming by downmodulating an early CD8 T-cell-mediated “negative feedback” control of the infection in the cortical region of the RLN, thus supporting the model that immunoevasins improve antigen supply for indirect priming by uninfected antigen-presenting cells. As an important consequence, these findings predict that deletion of immunoevasin genes in a replicative vaccine virus is not a favorable option but may, rather, be counterproductive.

scholarly journals High-Throughput Sequence Analysis of Peripheral T-Cell Lymphomas Indicates Subtype-Specific Viral Gene Expression Patterns and Immune Cell Microenvironments

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Hani Nakhoul ◽  
Zhen Lin ◽  
Xia Wang ◽  
Claire Roberts ◽  
Yan Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cell ◽  
Immune Cell ◽  
Cell Lymphoma ◽  
Viral Gene Expression ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Viral Gene ◽  
T Cell Lymphomas

ABSTRACTCertain peripheral T-cell lymphomas (PTCLs) have been associated with viral infection, particularly infection with Epstein-Barr virus (EBV). However, a comprehensive virome analysis across PTCLs has not previously been reported. Here we utilized published whole-transcriptome RNA sequencing (RNA-seq) data sets from seven different PTCL studies and new RNA-seq data from our laboratory to screen for virus association, to analyze viral gene expression, and to assess B- and T-cell receptor diversity paradigms across PTCL subtypes. In addition to identifying EBV in angioimmunoblastic T-cell lymphoma (AITL) and extranodal NK/T-cell lymphoma (ENKTL), two PTCL subtypes with well-established EBV associations, we also detected EBV in several cases of anaplastic large-cell lymphoma (ALCL), and we found evidence of infection by the oncogenic viruses Kaposi’s sarcoma-associated herpesvirus and human T-cell leukemia virus type 1 in isolated PTCL cases. In AITLs, EBV gene expression analysis showed expression of immediate early, early, and late lytic genes, suggesting either low-level lytic gene expression or productive infection in a subset of EBV-infected B-lymphocyte stromal cells. Deconvolution of immune cell subpopulations demonstrated a greater B-cell signal in AITLs than in other PTCL subtypes, consistent with a larger role for B-cell support in the pathogenesis of AITL. Reconstructed T-cell receptor (TCR) and B-cell receptor (BCR) repertoires demonstrated increased BCR diversity in AITLs, consistent with a possible EBV-driven polyclonal response. These findings indicate potential alternative roles for EBV in PTCLs, in addition to the canonical oncogenic mechanisms associated with EBV latent infection. Our findings also suggest the involvement of other viruses in PTCL pathogenesis and demonstrate immunological alterations associated with these cancers.IMPORTANCEIn this study, we utilized next-generation sequencing data from 7 different studies of peripheral T-cell lymphoma (PTCL) patient samples to globally assess viral associations, provide insights into the contributions of EBV gene expression to the tumor phenotype, and assess the unique roles of EBV in modulating the immune cell tumor microenvironment. These studies revealed potential roles for EBV replication genes in some PTCL subtypes, the possible role of additional human tumor viruses in rare cases of PTCLs, and a role for EBV in providing a unique immune microenvironmental niche in one subtype of PTCLs. Together, these studies provide new insights into the understudied role of tumor viruses in PTCLs.

scholarly journals Motor Skills: Recruitment of Kinesins, Myosins and Dynein during Assembly and Egress of Alphaherpesviruses

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1622
Author(s):  
Duncan W. Wilson
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Infected Cell ◽  
Motor Skills ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Viral Gene ◽  
Challenging Problem ◽  
Genome Packaging ◽  
Initial Infection

The alphaherpesviruses are pathogens of the mammalian nervous system. Initial infection is commonly at mucosal epithelia, followed by spread to, and establishment of latency in, the peripheral nervous system. During productive infection, viral gene expression, replication of the dsDNA genome, capsid assembly and genome packaging take place in the infected cell nucleus, after which mature nucleocapsids emerge into the cytoplasm. Capsids must then travel to their site of envelopment at cytoplasmic organelles, and enveloped virions need to reach the cell surface for release and spread. Transport at each of these steps requires movement of alphaherpesvirus particles through a crowded and viscous cytoplasm, and for distances ranging from several microns in epithelial cells, to millimeters or even meters during egress from neurons. To solve this challenging problem alphaherpesviruses, and their assembly intermediates, exploit microtubule- and actin-dependent cellular motors. This review focuses upon the mechanisms used by alphaherpesviruses to recruit kinesin, myosin and dynein motors during assembly and egress.

scholarly journals HHV-6 in the Lymphoma Microenvironment: Both Chicken and Egg?

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1377-1377
Author(s):  
Genevieve M Crane ◽  
Dmitry Tychinin ◽  
Anton Karelin ◽  
Aleksandr Cherdintsev ◽  
Olga Kudryashova ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Stock Options ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Viral Gene Expression ◽  
T Cell Subsets ◽  
Viral Gene ◽  
Provision Of Services ◽  
Privately Held

Abstract While Epstein-Barr virus (EBV) and the Kaposi sarcoma herpesvirus (KSHV)/human herpesvirus (HHV) 8 have shown a definite association with lymphoproliferative disease, a role for the HHV-6 has been less clear. Similar to other herpesviruses, HHV-6 predominantly remains latent following initial infection, but can be reactivated during stress or immune suppression, and is the cause of roseola in young children. Existing as two distinct species, HHV-6B is more common, infecting ~90% of adults. HHV-6B, a T-lymphotropic virus, enters cells via CD134, a TNF receptor superfamily member, expressed on both naïve and CD4 +CD25 + T cells, leading to CD4 + lymphocyte depletion and impaired T cell activation. HHV-6 has been variably detected in classic Hodgkin (CHL) and T-cell lymphomas (TCL) by immunohistochemistry (IHC) and PCR with more recent data suggesting infection may be confined to tumor-associated lymphocytes. The specificity of these IHC antibodies is not well documented. The question remains whether HHV-6 in the tumor microenvironment of advanced disease is a consequence of immune dysfunction, or may play a more direct role in tumor initiation and progression by altering the tumor microenvironment. To address these questions, we evaluated HHV-6B viral gene expression patterns in lymphoma patient samples by RNA sequencing techniques. Following IRB approval, CHL, TCL, B-cell, and post-transplant lymphoproliferative disease (PTLD) cases were screened for potential HHV-6-association by IHC with an antibody against HHV-6 gp60/110 envelope glycoprotein (Millipore Sigma, MAB8537). Positive cases with available frozen tissue and adequate RNA (5) or sorted T-cell subsets from Hodgkin lymphoma (11) underwent bulk RNA-seq (rRNA depletion (Illumina), 50M reads/sample). Viral transcripts were identified by performing the Burrows-Wheeler Alignment by reference host alignment (to filter host and bad quality reads) followed by viral reference host alignment. Previous TCL databases with available RNAseq data were similarly evaluated. IHC analysis revealed 5/25 CHL, 34/52 TCL, 5/13 PTLD, 4/81 diffuse large B-cell lymphoma (DLBCL) and 2/28 follicular lymphoma (FL) with rare gp60/110-positive cells. This included 11 CHL cases with sorted T-cell subsets, of which one showed membranous and Golgi gp60/110 staining in background T-cells (25-year-old female, nodular sclerosis subtype, EBV-negative). Of these 11 CHL cases, RNAseq of T-cell subsets revealed a pattern of HHV-6B transcripts in only this case. Frozen tumor blocks were available from 5 additional cases with positive gp60/110 staining (2 CHL, 1 DLBCL, 1 FL and 1 PTLD), but RNAseq analysis did not identify any HHV-6B transcripts. Notably, these cases had dim cytoplasmic but not Golgi gp60/110 staining. RNA sequencing data derived from two independent TCL cohorts were analyzed for HHV-6B transcripts. Although no HHV-6B transcripts were detected via RNAseq in 20 angioimmunoblastic T-cell lymphoma samples from one TCL cohort, many had EBV-gene expression. HHV-6B transcripts were detected in two cases of anaplastic large cell lymphoma (ALCL) in a second TCL cohort (2/79 cases). High expression of the U67, U68, U79 and U90 genes was found, revealing overlap of the HHV-6B transcript expression between ALCL and CHL samples (Fig 1). Additionally, detection of two genes that could be driving tumor growth (U51, which encodes a G-protein receptor and U24, which inhibits proper T cell activation, reducing secretion of cytokines at infection site) demonstrates a specific viral gene expression pattern within the intratumor T-cell population. The potential presence of HHV-6B infection in the lymphoma microenvironment is controversial. To our knowledge, this is the first report conclusively demonstrating HHV-6B expression in CHL using RNAseq. Notably, the viral gene expression pattern seen in CHL overlaps with that found in two cases of ALCL, highlighting viral proteins of potential particular significance. These data may aid in development of a more reliable means of HHV-6B detection. For example, the immediate early gene U90, a transcriptional activator that may induce expression of both viral and cellular genes that affect the tumor microenvironment, was consistently expressed and may be a reliable marker of HHV-6B infection. Funding: HHV-6 Foundation Figure 1 Figure 1. Disclosures Tychinin: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Karelin: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Cherdintsev: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kudryashova: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Egorov: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Degryse: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Roth: Merck: Consultancy; Janssen: Consultancy. Roshal: Celgene: Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services. Rabadan: Genotwin: Other: Raul Rabadan is founder of Genotwin; AimedBio: Membership on an entity's Board of Directors or advisory committees. Elemento: Owkin: Consultancy, Other: Current equity holder; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; One Three Biotech: Consultancy, Other: Current equity holder; Janssen: Research Funding; Eli Lilly: Research Funding; Champions Oncology: Consultancy; AstraZeneca: Research Funding; Johnson and Johnson: Research Funding.

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