Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) infection was necessary but not sufficient for Kaposi's sarcoma (KS) development without other cofactors. Previously, we identified that both human immunodeficiency type 1 (HIV-1) Tat and herpes simplex virus 1 (HSV-1) were important cofactors reactivating KSHV from latency. Here, we further investigated the potential of herpes simplex virus 2 (HSV-2) to influence KSHV replication and examined the role of Tat in this procedure. We demonstrated that HSV-2 was a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particles in BCBL-1 cells. These results were further confirmed by an RNA interference experiment using small interfering RNA targeting KSHV Rta and a luciferase reporter assay testing Rta promoter-driven luciferase activity. Mechanistic studies showed that HSV-2 infection activated nuclear factor-kappa B (NF-κB) signaling pathway. Inhibition of NF-κB pathway enhanced HSV-2-mediated KSHV activation, whereas activation of NF-κB pathway suppressed KSHV replication in HSV-2-infected BCBL-1 cells. Additionally, ectopic expression of Tat enhanced HSV-2-induced KSHV replication. These novel findings suggest a role of HSV-2 in the pathogenesis of KS and provide the first laboratory evidence that Tat may participate HSV-2-mediated KSHV activation, implying the complicated pathogenesis of acquired immunodeficiency syndrome (AIDS)-related KS (AIDS-KS) patients.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) was first detected in Kaposi’s sarcoma (KS) tissues from a patient with acquired immunodeficiency syndrome (AIDS) by representational difference analysis [1]
To evaluate whether herpes simplex virus 2 (HSV-2) affected KSHV replication, we first determined the susceptibility of BCBL-1 cells to HSV-2
Studies from three groups demonstrated that HSV-2 and KSHV were associated in the prisoners of Italian and some areas in Africa, which suggest that HSV-2 infection contributed to sexual transmission of KSHV infection [18,19,20]
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) was first detected in Kaposi’s sarcoma (KS) tissues from a patient with acquired immunodeficiency syndrome (AIDS) by representational difference analysis [1]. KSHV has two different phases in its life cycle, latency and lytic replication. Once KSHV was reactivated from latency and entered the lytic cycle, most viral genes were expressed in an orderly fashion (immediate-early, early and late), leading to the production of infectious virions [6,7,8]. We and others demonstrated that several agents, such as human immunodeficiency virus type 1 (HIV-1) transactivating protein Tat, herpes simplex virus type 1 (HSV-1), human herpesvirus 6 (HHV-6), human cytomegalovirus (HCMV) and HIV-1, have been proved to be cofactors reactivating KSHV from latency [9,10,11,12,13]
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