Nectin-2 Acts as a Viral Entry Mediated Molecule That Binds to Human Herpesvirus 6B Glycoprotein B

Human herpesvirus 6B (HHV-6B) is a T-lymphotropic virus and the etiological agent of exanthem subitum. HHV-6B is present in a latent or persistent form after primary infection and is produced in the salivary glands or transmitted to this organ. Infected individuals continue to secrete the virus in their saliva, which is thus considered a source for virus transmission. HHV-6B primarily propagates in T cells because its entry receptor, CD134, is mainly expressed by activated T cells. The virus then spreads to the host’s organs, including the salivary glands, nervous system, and liver. However, CD134 expression is not detected in these organs. Therefore, HHV-6B may be entering cells via a currently unidentified cell surface molecule, but the mechanisms for this have not yet been investigated. In this study, we investigated a CD134-independent virus entry mechanism in the parotid-derived cell line HSY. First, we confirmed viral infection in CD134-membrane unanchored HSY cells. We then determined that nectin cell adhesion molecule 2 (nectin-2) mediated virus entry and that HHV-6B-insensitive T-cells transduced with nectin-2 were transformed into virus-permissive cells. We also found that virus entry was significantly reduced in nectin-2 knockout parotid-derived cells. Furthermore, we showed that HHV-6B glycoprotein B (gB) interacted with the nectin-2 V-set domain. The results suggest that nectin-2 acts as an HHV-6B entry-mediated protein.

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Role of dendritic cells infected with human herpesvirus 6 in virus transmission to CD4+ T cells

Virology ◽

10.1016/j.virol.2008.11.049 ◽

2009 ◽

Vol 385 (2) ◽

pp. 294-302 ◽

Cited By ~ 11

Author(s):

Masaya Takemoto ◽

Takayoshi Imasawa ◽

Koichi Yamanishi ◽

Yasuko Mori

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Virus Transmission ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Herpesvirus 6

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HIV-1TransInfection of CD4+T Cells by Professional Antigen Presenting Cells

Scientifica ◽

10.1155/2013/164203 ◽

2013 ◽

Vol 2013 ◽

pp. 1-30 ◽

Cited By ~ 15

Author(s):

Charles R. Rinaldo

Keyword(s):

T Cells ◽

Virus Replication ◽

Virus Transmission ◽

Antigen Presenting Cells ◽

Activated T Cells ◽

Infection Processes ◽

The Many ◽

Antigen Presenting ◽

Hiv 1 ◽

Virus Subtype

Since the 1990s we have known of the fascinating ability of a complex set of professional antigen presenting cells (APCs; dendritic cells, monocytes/macrophages, and B lymphocytes) to mediate HIV-1transinfection of CD4+T cells. This results in a burst of virus replication in the T cells that is much greater than that resulting from direct,cisinfection of either APC or T cells, ortransinfection between T cells. Such APC-to-T celltransinfection first involves a complex set of virus subtype, attachment, entry, and replication patterns that have many similarities among APC, as well as distinct differences related to virus receptors, intracellular trafficking, and productive and nonproductive replication pathways. The end result is that HIV-1 can sequester within the APC for several days and be transmitted via membrane extensions intracellularly and extracellularly to T cells across the virologic synapse. Virus replication requires activated T cells that can develop concurrently with the events of virus transmission. Further research is essential to fill the many gaps in our understanding of thesetransinfection processes and their role in natural HIV-1 infection.

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Accumulation of human T lymphotropic virus type I-infected T cells in the salivary glands of patients with human T lymphotropic virus type I-associated Sj�gren's syndrome

Arthritis & Rheumatism ◽

10.1002/1529-0131(199811)41:11<1972::aid-art12>3.0.co;2-m ◽

1998 ◽

Vol 41 (11) ◽

pp. 1972-1978 ◽

Cited By ~ 22

Author(s):

Yukiko Ohyama ◽

Seiji Nakamura ◽

Hideo Hara ◽

Masanori Shinohara ◽

Masanori Sasaki ◽

...

Keyword(s):

T Cells ◽

Salivary Glands ◽

Virus Type ◽

Type I ◽

T Lymphotropic Virus

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Identification of residues in the V domain of CD80 (B7-1) implicated in functional interactions with CD28 and CTLA4.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.667 ◽

1995 ◽

Vol 182 (3) ◽

pp. 667-675 ◽

Cited By ~ 31

Author(s):

C A Fargeas ◽

A Truneh ◽

M Reddy ◽

M Hurle ◽

R Sweet ◽

...

Keyword(s):

T Cells ◽

Molecular Level ◽

Cell Types ◽

Immunoglobulin Superfamily ◽

Activated T Cells ◽

Cell Surface Molecule ◽

Structural Requirements ◽

Hydrophobic Residues ◽

Related Molecule ◽

Functional Interactions

The CD80 (B7-1) molecule is a 45-60-kD member of the immunoglobulin superfamily that is expressed on a variety of cell types of haematopoietic origin. CD80 can provide a critical costimulatory signal to T cells by interacting with the T cell surface molecule CD28. CD80 also binds to the CD28-related molecule CTLA4, which is expressed on activated T cells, Recently, additional ligands of CD28 and CTLA4 have been described in mice and humans. One of them, CD86 (B-70 or B7-2) was characterized at the molecular level. Although similar in predicted structure to CD80, it is distantly related in amino acid sequence. In this study, human CD80 mutants were generated and tested for their ability to maintain the interaction with CD28 leading to adhesion and enhanced IL-2 production. Two hydrophobic residues in the V-like domain of CD80 were identified as critical for binding to CD28 and are also important for the interaction with CTLA4. These residues are adjacent to the epitope of the BB1 antibody, which inhibits CD28-CD80 interactions. One of these residues, Y87, is conserved in all CD80 and CD86 cloned from various species. These results being to unravel the structural requirements for binding to CD28 and CTLA4.

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Immediate Activation Fails To Rescue Efficient Human Immunodeficiency Virus Replication in Quiescent CD4+ T Cells

Journal of Virology ◽

10.1128/jvi.02569-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3574-3582 ◽

Cited By ~ 50

Author(s):

Dimitrios N. Vatakis ◽

Gregory Bristol ◽

Thomas A. Wilkinson ◽

Samson A. Chow ◽

Jerome A. Zack

Keyword(s):

Cell Cycle ◽

Human Immunodeficiency Virus ◽

T Cells ◽

Life Cycle ◽

Viral Entry ◽

Viral Protein ◽

Brdu Incorporation ◽

Human Immunodeficiency Virus Replication ◽

Activated T Cells ◽

Immunodeficiency Virus

ABSTRACT Unlike activated T cells, quiescent CD4+ T cells have shown resistance to human immunodeficiency virus (HIV) infection due to a block in the early events of the viral life cycle. To further investigate the nature of this block, we infected quiescent CD4+ T cells with HIV-1NL4-3 and immediately stimulated them. Compared to activated (prestimulated) cells, these poststimulated cells showed slightly decreased viral entry and delays in the completion of reverse transcription. However, the relative efficiency of integration was similar to that of prestimulated cells. Together, this resulted in decreased expression of tat/rev mRNA and synthesis of viral protein. Furthermore, based on cell cycle staining and BrdU incorporation, poststimulated cells expressing viral protein failed to initiate a second round of their cell cycle, independently of Vpr-mediated arrest. Together, these data demonstrate that the early stages of the HIV life cycle are inefficient in these poststimulated cells and that efficient replication cannot be induced by subsequent activation.

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Human herpesvirus 6 envelope cholesterol is required for virus entry

Journal of General Virology ◽

10.1099/vir.0.81551-0 ◽

2006 ◽

Vol 87 (2) ◽

pp. 277-285 ◽

Cited By ~ 40

Author(s):

Honglan Huang ◽

Yongmei Li ◽

Tomohiko Sadaoka ◽

Huanmin Tang ◽

Takahito Yamamoto ◽

...

Keyword(s):

Cell Fusion ◽

Viral Entry ◽

Virus Entry ◽

Human Herpesvirus ◽

Fusion Process ◽

Cholesterol Depletion ◽

Human Herpesvirus 6 ◽

Exogenous Cholesterol ◽

Herpesvirus 6

In this study, the role of cholesterol in the envelope of human herpesvirus 6 (HHV-6) was examined by using methyl-β-cyclodextrin (MβCD) depletion. When cholesterol was removed from HHV-6 virions with MβCD, infectivity was abolished, but it could be rescued by the addition of exogenous cholesterol. HHV-6 binding was affected slightly by MβCD treatment. In contrast, envelope cholesterol depletion markedly affected HHV-6 infectivity and HHV-6-induced cell fusion. These results suggest that the cholesterol present in the HHV-6 envelope plays a prominent role in the fusion process and is a key component in viral entry.

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Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12I

Journal of Virology ◽

10.1128/jvi.76.7.3493-3501.2002 ◽

2002 ◽

Vol 76 (7) ◽

pp. 3493-3501 ◽

Cited By ~ 47

Author(s):

Björn Albrecht ◽

Celine D. D'Souza ◽

Wei Ding ◽

Susheela Tridandapani ◽

K. Mark Coggeshall ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Persistent Infection ◽

Lymphocyte Activation ◽

Accessory Protein ◽

Nuclear Factor ◽

Activated T Cells ◽

T Lymphotropic Virus ◽

Calcium Dependent

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4+ T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12I is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12I in lymphocyte activation. To test whether p12I modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-κB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12I-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12I specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-κB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N′-1,2-ethanediylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12I-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-γ and LAT (linker for activation of T cells) did not affect p12I-induced NFAT activity. Importantly, p12I functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12I in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.

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Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2355 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2355-2360 ◽

Cited By ~ 33

Author(s):

S Noda ◽

A Kosugi ◽

S Saitoh ◽

S Narumiya ◽

T Hamaoka

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Activated T Cells ◽

Cell Surface Molecule ◽

Newborn Mice ◽

Cell Antigen ◽

Peripheral T Cells ◽

Induced Apoptosis

During T cell development in the thymus, the expression of thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+ CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8- thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T cells is induced upon activation and that anti-TSA-1 mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In the present study, we have analyzed a role of TSA-1 in thymic selection events, especially in TCR-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected into newborn mice in vivo together with anti-CD3 epsilon or anti-TCR-beta, TCR/CD3-mediated apoptosis of thymocytes was almost completely blocked. The blockade of apoptosis was defined by the inhibition of, first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4+ CD8+ thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1 did not block either steroid- or radiation-induced apoptosis, indicating that a signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a developing T cell.

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Human Herpesvirus 8-Encoded vGPCR Activates Nuclear Factor of Activated T Cells and Collaborates with Human Immunodeficiency Virus Type 1 Tat

Journal of Virology ◽

10.1128/jvi.77.10.5759-5773.2003 ◽

2003 ◽

Vol 77 (10) ◽

pp. 5759-5773 ◽

Cited By ~ 43

Author(s):

Shibani Pati ◽

James S. Foulke ◽

Oxana Barabitskaya ◽

Jynho Kim ◽

B. C. Nair ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Human Herpesvirus ◽

Human Herpesvirus 8 ◽

Nuclear Factor ◽

Activated T Cells ◽

Herpesvirus 8 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi's sarcoma (KS), encodes a chemokine receptor homologue, the viral G protein-coupled receptor (vGPCR), that has been implicated in KS pathogenesis. Expression of vGPCR constitutively activates several signaling pathways, including NF-κB, and induces the expression of proinflammatory and angiogenic factors, consistent with the inflammatory hyperproliferative nature of KS lesions. Here we show that vGPCR also constitutively activates the nuclear factor of activated T cells (NF-AT), another transcription factor important in regulation of the expression of inflammatory cytokines and related factors. NF-AT activation by vGPCR depended upon signaling through the phosphatidylinositol 3-kinase-Akt-glycogen synthetase kinase 3 (PI3-K/Akt/GSK-3) pathway and resulted in increased expression of NF-AT-dependent cell surface molecules (CD25, CD29, Fas ligand), proinflammatory cytokines (interleukin-2 [IL-2], IL-4), and proangiogenic factors (granulocyte-macrophage colony-stimulating factor GMCSF and TNFα). vGPCR expression also increased endothelial cell-T-cell adhesion. Although infection with HHV-8 is necessary to cause KS, coinfection with human immunodeficiency virus type 1 (HIV-1), in the absence of antiretroviral suppressive therapy, increases the risk of KS by many orders of magnitude. NF-AT and NF-κB activation by vGPCR was greatly increased by the HIV-1 Tat protein, although Tat alone had little effect on NF-AT. The enhancement of NF-AT by Tat appears to be mediated through collaborative stimulation of the PI3-K/Akt/GSK-3 pathway by vGPCR and Tat. Our data further support the idea that vGPCR contributes to the pathogenesis of KS by a paracrine mechanism and, in addition, provide the first evidence of collaboration between an HIV-1 protein and an HHV-8 protein.

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