| Kaposi's sarcoma-associated herpesvirus (KSHV) infection appears to be necessary but not sufficient for Kaposi's sarcoma (KS) development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we identified that both human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1) Tat were important cofactors that activated lytic cycle replication of KSHV. Here, we further investigated the potential of human herpes simplex virus-1 (HSV-1) to influence KSHV replication. We demonstrated that HSV-1 was a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particls in BCBL-1 cells. These results were further confirmed by a luciferase reporter assay testing ORF50 promoter-driven luciferase activity and an RNA interference experiment using small interfering RNA (siRNA) targeting KSHV ORF50. Studies on mechanism showed that HSV-1 induced the production of interleukin-10 (IL-10) and its receptor (IL-10Rα), interleukin-4 (IL-4) and its receptor (IL-4R). Neutralization of IL-10 or IL-4 with corresponding neutralizing antibodies decreased the lytic cycle replication of KSHV by HSV-1. In addition, IL-10/IL-10Ra and IL-4/IL-4R from HSV-1-infected BCBL-1 cells activated PI3K/AKT, ERK MAPK and JAK2 signalings. Addition of LY294002, PI3K inhibitor, peptide II, ERK inhibitor and AG490, JAK2 inhibitor into cell culture significantly decreased the lytic replication of KSHV by HSV-1. These findings suggest that HSV-1 may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. IL-10,IL-4 and their signalings played an important role in modulation of HSV-1-induced KSHV replication. These data also suggest that the blockage of PI3K/AKT, ERK MAPK and JAK2 signalings may be of therapeutic value in KS patients.
|
PDF Full Text Request