Kaposi's Sarcoma‐associated Herpesvirus—Antiviral Treatment

Schulz, Thomas F.

doi:10.1002/9783527810697.ch8

Cited by 1 publication

(3 citation statements)

References 223 publications

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“…KSHV is the etiological agent responsible for several human diseases including Kaposi's sarcoma (KS), Multicentric Castleman's Disease (MCD), Primary Effusion Lymphomas (PEL) and KSHV inflammatory cytokine syndrome (1-4). Drugs currently used to treat KSHV associated malignancies are at best moderately effective and therapies for related human herpesviruses have been shown to be ineffective (5)(6)(7)(8)(9). A specific cure or vaccine for the treatment or prevention of KSHV has not yet been approved for clinical use (5,6,10).…”

Section: Introductionmentioning

confidence: 99%

“…Drugs currently used to treat KSHV associated malignancies are at best moderately effective and therapies for related human herpesviruses have been shown to be ineffective (5)(6)(7)(8)(9). A specific cure or vaccine for the treatment or prevention of KSHV has not yet been approved for clinical use (5,6,10). Given the endemic spread of the disease in Africa, and prevalence in transplant and HIV-infected patients, there is still a need for novel KSHV therapeutic targets (5,9).…”

Section: Introductionmentioning

confidence: 99%

“…A specific cure or vaccine for the treatment or prevention of KSHV has not yet been approved for clinical use (5,6,10). Given the endemic spread of the disease in Africa, and prevalence in transplant and HIV-infected patients, there is still a need for novel KSHV therapeutic targets (5,9). Herpesviruses contain a double stranded DNA genome and encode their own DNA replication proteins that are essential for successful viral production and dissemination.…”

Section: Introductionmentioning

confidence: 99%

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Electron microscopy mapping of the DNA-binding sites of monomeric, dimeric, and multimeric KSHV RTA protein

Calhoun¹,

Damania

Griffith

et al. 2023

Preprint

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Molecular interactions between viral DNA and viral-encoded protein are a prerequisite for successful herpesvirus replication and production of new infectious virions. Here, we examined how the essential Kaposi's sarcoma-associated herpesvirus (KSHV) protein, RTA, binds to viral DNA using transmission electron microscopy (TEM). Previous studies using gel-based approaches to characterize RTA binding are important for studying the predominant form(s) of RTA within a population and identifying the DNA sequences that RTA binds with high affinity. However, using TEM we were able to examine individual protein-DNA complexes and capture the various oligomeric states of RTA when bound to DNA. Hundreds of images of individual DNA and protein molecules were collected and then quantified to map the DNA binding positions of RTA bound to the two KSHV lytic origins of replication encoded within the KSHV genome. The relative size of RTA or RTA bound to DNA were then compared to protein standards to determine whether RTA complexed with DNA was monomeric, dimeric, or formed larger oligomeric structures. We successfully analyzed a highly heterogenous dataset and identified new binding sites for RTA. This provides direct evidence that RTA forms dimers and high order multimers when bound to KSHV origin of replication DNA sequences. This work expands our understanding of RTA binding, and demonstrates the importance of employing methodologies that can characterize highly heterogenic populations of proteins.

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