Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency

Wheat, William H.; Cool, Carlyne D.; Morimoto, Yoshikazu; Pradeep, Roshini; Kirkpatrick, Charles H.; Lindenbaum, Barbara A.; Bates, Christopher A.; Ellison, Misoo C.; Serls, Amanda E.; Brown, Kevin K.; Routes, John M.

doi:10.1084/jem.20050381

Cited by 144 publications

(75 citation statements)

References 27 publications

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“…In light of our findings, it is notable that KSHV infection is also associated with a granulomatous/lymphocytic interstitial lung disease in patients with common variable immunodeficiency (47). Here, as in infected wood mice, virus antigenpositive lymphocytes are present in interstitial foci within the lung.…”

Section: Discussionsupporting

confidence: 56%

Pathogenesis of a Model Gammaherpesvirus in a Natural Host

Hughes

Kipar

Sample

et al. 2010

J Virol

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Murine gammaherpesvirus 68 (MHV-68) infection of laboratory mice (Mus musculus) is an established model of gammaherpesvirus pathogenesis. The fact that M. musculus is not a host in the wild prompted us to reassess MHV-68 infection in wood mice (Apodemus sylvaticus), a natural host. Here, we report significant differences in MHV-68 infection in the two species: (i) following intranasal inoculation, MHV-68 replicated in the lungs of wood mice to levels approximately 3 log units lower than in BALB/c mice; (ii) in BALB/c mice, virus replication in alveolar epithelial cells was accompanied by a diffuse, T-cell-dominated interstitial pneumonitis, whereas in wood mice it was restricted to focal granulomatous infiltrations; (iii) within wood mice, latently infected lymphocytes were abundant in inducible bronchus-associated lymphoid tissue that was not apparent in BALB/c mice; (iv) splenic latency was established in both species, but well-delineated secondary follicles with germinal centers were present in wood mice, while only poorly delineated follicles were seen in BALB/c mice; and, perhaps as a consequence, (v) production of neutralizing antibody was significantly higher in wood mice. These differences highlight the value of this animal model in the study of MHV-68 pathogenesis.

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Section: Discussionsupporting

confidence: 56%

Pathogenesis of a Model Gammaherpesvirus in a Natural Host

Hughes

Kipar

Sample

et al. 2010

J Virol

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“…17 In CVID patients with granulomatous disease, an underlying viral infection has been suggested by several groups. 18,19 In a small study, human herpes virus 8 (HHV8) 19 infection was detectable in 6 of 9 patients with granulomatous and or interstitial lung disease, whereas the virus was found in only 1 CVID patient without apparent granulomatous disease and was undetectable in all controls. Unfortunately, no data are available on the B-cell phenotype of these patients.…”

Section: Discussionmentioning

confidence: 99%

The EUROclass trial: defining subgroups in common variable immunodeficiency

Wehr

Kivioja

Schmitt

et al. 2008

Blood

724

697

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IntroductionCommon variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. 1 Recurrent bacterial infections of the respiratory tract are the clinical hallmark present in nearly all patients. 2 In addition, up to 40% of the patients show gastrointestinal disease, concomitant lymphoproliferative disorders, autoimmune phenomena, or granulomatous inflammation. 2 The pathogenic understanding of antibody deficiency in humans has always been hampered by the great heterogeneity of the syndrome. 3 In 1966, Rosen and Janeway started to group antibody deficiencies by their mode of inheritance. 4 In 1973, Cooper included the clinical course and serum immunoglobulin levels, thereby separating hyper-IgM syndromes and selective IgA deficiency. 5 The remaining group of still very heterogeneous antibody deficiencies was termed CVID. Consecutive attempts to subclassify CVID by B-cell function in vitro 6,7 failed to reach diagnostic acceptance because of laborious and poorly standardized procedures and a lack of clinical relevance.In 2002, we and others suggested a flow cytometric classification of CVID according to the B-cell phenotype. 8,9 The abnormalities of circulating B cells in patients with CVID had already been recognized earlier, 10 but only with the ease and the broad availability of flow cytometry was a widespread and systematic analysis of these aberrations possible. The Freiburg classification divided patients into 3 groups by analyzing the expression of IgM, IgD, CD27 and CD21. 8 Group 1 was characterized by a severe reduction of switched memory B cells (IgD Ϫ IgM Ϫ CD27 ϩ less than 0.4% of lymphocytes), while group 2 representing 25% of the analyzed CVID patients exhibited nearly normal numbers of class-switched memory B cells, suggesting a post germinal center defect. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Methods PatientsAll patients were diagnosed as having CVID based on the European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency (ESID/PAGID) criteria, 11 including a marked decrease of IgG (at least 2 standard deviations [SDs] below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, the onset of clinical significant immunodeficiency at greater than 2 years of age, and the exclusion of defined causes of hypogammaglobulinemia (see also www.esid.org). Not all patients have been evaluated for absent isohemagglutinins and/or poor response to vaccines. For the final evaluation of B-cell phenotyping, the following exclusion criteria were adopted: patients younger than 6 years of age at the time of flowcytometric evaluation, patients on immunosuppressive treatment, patients suffering currently from malignancies, and patients with less than 1% peripheral B cells. Altogether, 303 patients of origi...

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“…KSHV is believed to be the etiological agent of several human cancers, including KS (1, 2), primary effusion lymphoma (PEL) or body cavity based lymphoma (3), and multicentric Castleman's disease (MCD) (4,5). Additionally, there have been reports of KSHV-associated solid lymphomas in HIV-positive and -negative patients as well as KSHV-associated lymphomas in patients with primary immune deficiencies, such as common variable immune deficiency (6,7). Similar to other members of the gammaherpesvirus family, KSHV establishes a predominantly latent infection in host cells after primary infection (8).…”

mentioning

confidence: 99%

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Sun

Jha

Robertson

2015

J Virol

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Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. IMPORTANCEDuring latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. K aposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8, an oncogenic member of the gammaherpesvirus subfamily, was first identified in 1994 from body cavity-based lymphoma (BCBL) and HIV-infected patients with Kaposi's sarcoma (KS) (1). KSHV is believed to be the etiological agent of several human cancers, including KS (1, 2), primary effusion lymphoma (PEL) or body cavity based lymphoma (3), and multicentric Castleman's disease (MCD) (4, 5). Additionally, there have been reports of KSHV-associated solid lymphomas in HIV-positive and -negative patients as well as KSHV-associated lymphomas in patients with primary immune deficiencies, such as common variable immune deficiency (6, 7). Similar to other members of the gammaherpesvirus family, KSHV establishes a predominantly latent infection in host cells after primary infection (8). During latent infections, the KSHV genome persists as a circular doublestranded DNA (episome) with most viral genes being silenced, except for a small number of latent genes, which include the viral cyclin (v-cyclin), the latency-associated nuclear antigen (LANA), and the viral FLICE inhibitory prote...

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Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency

Cited by 144 publications

References 27 publications

Pathogenesis of a Model Gammaherpesvirus in a Natural Host

Pathogenesis of a Model Gammaherpesvirus in a Natural Host

The EUROclass trial: defining subgroups in common variable immunodeficiency

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

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