Usefulness of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) DNA Viral Load in Whole Blood for Diagnosis and Monitoring of KSHV-Associated Diseases

Abstract Background Detectable Kaposi’s sarcoma–associated herpesvirus (KSHV) DNA in blood and increased antibody titres may indicate KSHV reactivation, while the transmission of KSHV occurs via viral shedding in saliva. Methods We investigated the risk factors for KSHV DNA detection by real-time polymerase chain reaction in blood and by viral shedding in saliva, in 878 people aged 3 to 89 years of both sexes in a rural Ugandan population cohort. Helminths were detected using microscopy and the presence of malaria parasitaemia was identified using rapid diagnostic tests. Regression modelling was used for a statistical analysis. Results The KSHV viral load in blood did not correlate with the viral load in saliva, suggesting separate immunological controls within each compartment. The proportions of individuals with a detectable virus in blood were 23% among children aged 3–5 years and 22% among those 6–12 years, thereafter reducing with increasing age. The proportions of individuals with a detectable virus in saliva increased from 30% in children aged 3–5 years to 45% in those aged 6–12 years, and decreased subsequently with increasing age. Overall, 29% of males shed in saliva, compared to 19% of females (P = .008). Conclusions Together, these data suggest that young males may be responsible for much of the onward transmission of KSHV. Individuals with a current malaria infection had higher levels of viral DNA in their blood (P = .031), compared to uninfected individuals. This suggests that malaria may lead to KSHV reactivation, thereby increasing the transmission and pathogenicity of the virus.

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Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01259-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 563-573 ◽

Cited By ~ 15

Author(s):

Bo Xu ◽

Ling Wang ◽

Lorenzo González-Molleda ◽

Yan Wang ◽

Jun Xu ◽

...

Keyword(s):

Kaposi's Sarcoma ◽

Topoisomerase Ii ◽

Primary Effusion Lymphoma ◽

Kaposi’S Sarcoma ◽

Binding Mode ◽

Lytic Replication ◽

Associated Diseases ◽

Catalytic Inhibitor ◽

Kaposi's Sarcoma Associated Herpesvirus ◽

Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACTKaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection.

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