Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Monocytes Downregulates Expression of Adaptive Immune Response Costimulatory Receptors and Proinflammatory Cytokines

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Journal of Virology (Impact Factor: 4.44). 01/2012; 86(7):3916-23. DOI: 10.1128/JVI.06437-11
Source: PubMed


Kaposi's sarcoma-associated herpesvirus (KSHV) infection is associated with the development of Kaposi's sarcoma, primary effusion
lymphoma, and multicentric Castleman's disease. We report the establishment of a monocytic cell line latently infected with
KSHV (KSHV-THP-1). We profiled viral and cytokine gene expression in the KSHV-THP-1 cells compared to that in uninfected THP-1
cells and found that several genes involved in the host immune response were downregulated during latent infection, including
genes for CD80, CD86, and the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Thus, KSHV minimizes
its immunological signature by suppressing key immune response factors, enabling persistent infection and evasion from host

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    • "Previous studies by our group demonstrate that HHV-8 infection of MDDC in vitro reduces their level of endocytosis as well as inhibits their ability to activate virus-specific CD8 + T cells (Rappocciolo et al., 2006a). In addition, Gregory et al. (2012) established latent HHV-8 infection of a monocyte cell line in vitro as a model to study the impact of HHV-8 on monocyte function. Latent viral infection of the monocyte cell line was associated with a dampened inflammatory and adaptive immune response, indicated by a decrease in proinflammatory cytokine production and monocyte co-stimulatory molecule expression associated with T cell activation. "
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    ABSTRACT: Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is an oncogenic gammaherpesvirus that primarily infects cells of the immune and vascular systems. HHV-8 interacts with and targets professional antigen presenting cells and influences their function. Infection alters the maturation, antigen presentation, and immune activation capabilities of certain dendritic cells (DC) despite non-robust lytic replication in these cells. DC sustains a low level of antiviral functionality during HHV-8 infection in vitro. This may explain the ability of healthy individuals to effectively control this virus without disease. Following an immune compromising event, such as organ transplantation or human immunodeficiency virus type 1 infection, a reduced cellular antiviral response against HHV-8 compounded with skewed DC cytokine production and antigen presentation likely contributes to the development of HHV-8 associated diseases, i.e., Kaposi's sarcoma and certain B cell lymphomas. In this review we focus on the role of DC in the establishment of HHV-8 primary and latent infection, the functional state of DC during HHV-8 infection, and the current understanding of the factors influencing virus-DC interactions in the context of HHV-8-associated disease.
    Full-text · Article · Aug 2014 · Frontiers in Microbiology
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    • "KSHV is able to infect a variety of non haematological and haematological cells such as B and T lymphocytes, monocytes, macrophages and dendritic cells (DC) that express the known KSHV receptors [2-6], such as proteoglycan heparan sulphates (HS), DC-SIGN and some integrins [7-10]. THP-1 is a monocytic cell line derived from an acute monocytic leukemia patient whose infection by KSHV has been previously reported [11,12]. These cells support a latent viral infection that implies the expression of few viral proteins in the majority of the infected cells that is sufficient to subvert the expression of monocyte activation markers and influence the cytokine release [12]. "
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    ABSTRACT: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates multiple cellular processes such as cell proliferation, evasion from apoptosis, migration, glucose metabolism, protein synthesis and proper differentiation in immune cells. Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several human malignancies, expresses a variety of latent and lytic proteins able to activate PI3K/AKT pathway, promoting the growth of infected cells and a successful viral infection. We found that KSHV latent infection of THP-1 cells, a human monocytic cell line derived from an acute monocytic leukemia patient, resulted in an increase of AKT phoshorylation, not susceptible to bortezomib-induced dephosphorylation, compared to the mock-infected THP-1. Accordingly, THP-1-infected cells displayed increased resistance to the bortezomib cytotoxic effect in comparison to the uninfected cells, which was counteracted by pre-treatment with AKT-specific inhibitors. Finally, AKT hyperactivation by KSHV infection correlated with plasma membrane exposure of glucose transporter GLUT1, particularly evident during bortezomib treatment. GLUT1 membrane trafficking is a characteristic of malignant cells and underlies a change of glucose metabolism that ensures the survival to highly proliferating cells and render these cells highly dependent on glycolysis. GLUT1 membrane trafficking in KSHV-infected THP-1 cells indeed led to increased sensitivity to cell death induced by the glycolysis inhibitor 2-Deoxy-D-glucose (2DG), further potentiated by its combination with bortezomib. KSHV confers to the THP-1 infected cells an oncogenic potential by altering the phosphorylation, expression and localization of key molecules that control cell survival and metabolism such as AKT and GLUT1. Such modifications in one hand lead to resistance to cell death induced by some chemotherapeutic drugs such as bortezomib, but on the other hand, offer an Achilles heel, rendering the infected cells more sensitive to other treatments such as AKT or glycolysis inhibitors. These therapeutic strategies can be exploited in the anticancer therapy of KSHV-associated malignancies.
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    No preview · Article · Jul 2012 · Future Microbiology
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