Persistent Infection of Epstein-Barr Virus-Positive B Lymphocytes by Human Herpesvirus 8

Kliche, Stefanie; Kremmer, Elisabeth; Hammerschmidt, Wolfgang; Koszinowski, Ulrich H.; Haas, Jürgen

doi:10.1128/jvi.72.10.8143-8149.1998

Cited by 52 publications

(10 citation statements)

References 46 publications

(48 reference statements)

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“…Flow cytometric analysis demonstrates that KSHV replicates primarily in CD19 + B cell populations of the implant, which is consistent with the tropism described for KSHV in humans 47515253. As KSHV does not replicate in SCID mice 30 that have received human peripheral blood leukocytes (a model that does not support hematopoiesis; reference 29), our observations suggest that immature or developing cell populations may serve as the predominant target of KSHV infection.…”

Section: Discussionsupporting

confidence: 84%

Experimental Transmission of Kaposi's Sarcoma–Associated Herpesvirus (Kshv/Hhv-8) to Scid-Hu Thy/Liv Mice

Dittmer

Stoddart

Renne

et al. 1999

The Journal of Experimental Medicine

100

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Kaposi's sarcoma–associated herpesvirus (KSHV/HHV-8) is a novel human lymphotropic herpesvirus linked to several human neoplasms. To date, no animal model for infection by this virus has been described. We have examined the susceptibility of C.B-17 scid/scid mice implanted with human fetal thymus and liver grafts (SCID-hu Thy/Liv mice) to KSHV infection. KSHV virions were inoculated directly into the implants, and viral DNA and mRNA production was assayed using real-time quantitative polymerase chain reaction. This revealed a biphasic infection, with an early phase of lytic replication accompanied and followed by sustained latency. Ultraviolet irradiation of the inoculum abolished all DNA- and mRNA-derived signals, and infection was inhibited by ganciclovir. Viral gene expression was most abundant in CD19+ B lymphocytes, suggesting that this model faithfully mimics the natural tropism of this virus. Short-term coinfection with HIV-1 did not alter the course of KSHV replication, nor did KSHV alter levels of HIV-1 p24 during the acute phase of the infection. Although no disease was evident in infected animals, SCID-hu Thy/Liv mice should allow the detailed study of KSHV tropism, latency, and drug susceptibility.

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Section: Discussionsupporting

confidence: 84%

Experimental Transmission of Kaposi's Sarcoma–Associated Herpesvirus (Kshv/Hhv-8) to Scid-Hu Thy/Liv Mice

Dittmer

Stoddart

Renne

et al. 1999

The Journal of Experimental Medicine

100

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“…In summary, KSHV persists in the majority of huNSG mice upon infection with EBV, and dual infection leads to a higher EBV burden, increased tumor formation, and reduced survival. Furthermore, both viruses can frequently be found in the same cells, in line with previously reported KSHV infection of EBV transformed B cells in vitro (Kliche et al, 1998).…”

Section: Kshv Persists More Frequently In the Presence Of Ebv In Hunssupporting

confidence: 88%

Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

McHugh

Caduff

Barros

et al. 2017

Cell Host & Microbe

108

158

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The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.

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“…Other BLs, particularly from HIV + patients, do not carry EBV but nevertheless grow readily in culture or form tumors in nude mice. Some BLs, such as BJAB, can be infected with either EBV or KSHV post facto (67,68), and some EBV + LCL cell lines can be infected with KSHV (69); under either scenario the addition of the virus does not change the proliferative potential of these cells. This suggests the presence of two evolutionary pathways toward the development of PEL, one that is absolutely dependent on the presence of EBV coinfection and another that is not.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus

Bigi

Landis

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi's sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein-Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV + single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV + /EBV + PEL cell lines with an EBV-specific CRISPR/ Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein-Barr nuclear antigen 1 (EBNA-1) in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.O ne almost never finds two different viruses in the same cell. SignificancePrimary effusion lymphoma (PEL) is a B cell lymphoma; the prognosis is poor, with a median survival around 6 months. PEL is always associated with the presence of Kaposi's sarcomaassociated herpesvirus and in most cases is coinfected with Epstein-Barr virus (EBV); however, the role of EBV in the pathogenesis of the tumor is still not clear. This study demonstrates the intricate interaction between the two herpesviruses, which exacerbate tumorigenesis by mutually reinforcing the persistence of each latent genome and by altering cell proliferation. It establishes curing EBV and inhibiting Epstein-Barr nuclear antigen 1 as a potential treatment for PEL.

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Persistent Infection of Epstein-Barr Virus-Positive B Lymphocytes by Human Herpesvirus 8

Cited by 52 publications

References 46 publications

Experimental Transmission of Kaposi's Sarcoma–Associated Herpesvirus (Kshv/Hhv-8) to Scid-Hu Thy/Liv Mice

Experimental Transmission of Kaposi's Sarcoma–Associated Herpesvirus (Kshv/Hhv-8) to Scid-Hu Thy/Liv Mice

Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

Epstein–Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus

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