KSHV: forgotten but not gone

Moore, Patrick S.; Chang, Yuan

doi:10.1182/blood-2011-05-350306

Cited by 11 publications

(10 citation statements)

References 8 publications

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“…Currently, there are not many effective methods available for the treatment of KSHV infection ( 16 , 17 ). At present, anti-herpesvirus therapies are mostly aimed to selectively inhibit the lytic DNA replication of the virus ( 16 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

“…For this reason, although antiretroviral therapy reduces the symptoms of the KSHV during latency, they do not reduce copies of latently persisting KSHV genomes from the infected cells ( 19 , 20 ). Since KSHV, like other herpesviruses, establishes life-long latent infection by escaping the host's immune surveillance system, it is not yet possible to eliminate the virus from the infected individual ( 17 , 21 – 23 ). Hence, disrupting KSHV latency will be a crucial step in the elimination of the virus from the infected host cells ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

Madireddy

Purushothaman

Loosbroock

et al. 2016

Nucleic Acids Research

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Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated nuclear antigen (LANA), which binds in the terminal repeat (TR) region of the viral genome. Sequence analysis of the TR, a GC-rich DNA element, identified several potential Quadruplex G-Rich Sequences (QGRS). Since quadruplexes have the tendency to obstruct DNA replication, we used G-quadruplex stabilizing compounds to examine their effect on latent DNA replication and the persistence of viral episomes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dormant origins of DNA replication, with preferential bi-directional pausing of replications forks moving out of the TR region, implicating the role of the G-rich TR in the perturbation of episomal DNA replication. Over time, treatment with PhenDC3 showed a loss of viral episomes in the infected cells. Overall, these data show that G-quadruplex stabilizing compounds retard the progression of replication forks leading to a reduction in DNA replication and episomal maintenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV-associated diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

Madireddy

Purushothaman

Loosbroock

et al. 2016

Nucleic Acids Research

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“…Upon reactivation from latency, most viral genes are expressed in an orderly fashion, leading to production of infectious virions. Since viral reactivation also results in host cell destruction in vitro , lytic induction of latent KSHV is considered to be a potential therapeutic option for treatment of KSHV-associated malignancies [8,9]. Many antiviral drugs, such as ganciclovir, valproic acid, bortezomib, prostratin, anthracycline and celecoxib, are based on the target of lytic replication [10–15].…”

Section: Introductionmentioning

confidence: 99%

Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma

Ding¹,

Zhu²,

Zhou³

et al. 2019

PLoS Pathog

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Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy without effective treatment, and caused by the infection of Kaposi’s sarcoma-associated herpesvirus (KSHV), predominantly in its latent form. Previously we showed that the SUMO2-interacting motif within the viral latency-associated nuclear antigen (LANASIM) is essential for establishment and maintenance of KSHV latency. Here, we developed a luciferase based live-cell reporter system to screen inhibitors selectively targeting the interaction between LANASIM and SUMO2. Cambogin, a bioactive natural product isolated from the Garcinia genus (a traditional herbal medicine used for cancer treatment), was obtained from the reporter system screening to efficiently inhibit the association of SUMO2 with LANASIM, in turn reducing the viral episome DNA copy number for establishment and maintenance of KSHV latent infection at a low concentration (nM). Importantly, Cambogin treatments not only specifically inhibited proliferation of KSHV-latently infected cells in vitro, but also induced regression of PEL tumors in a xenograft mouse model. This study has identified Cambogin as a novel therapeutic agent for treating PEL as well as eliminating persistent infection of oncogenic herpesvirus.

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“…Many antiviral drugs currently used to target KSHV are based on the inhibition of lytic replication [10]. For example, gancyclovir (GCV) is a nucleoside analog that is modified by viral proteins and eventually inhibits viral DNA polymerase activity [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Efficient lytic induction of kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines

et al. 2014

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Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection.

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KSHV: forgotten but not gone

Cited by 11 publications

References 8 publications

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma

Efficient lytic induction of kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines

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