Role Of JAK/STAT Signaling In Reactivation Of Kaposi's Sarcoma-Associated Herpesvirus From Latency By Intracellular Tat Of Human Immunodeficiency Virus Type 1

Human immunodeficiency virus type 1 (HIV-1) infectionsignificantly increases the risk of Kaposi's sarcoma (KS) occurrence inindividuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV).KSHV infection appears to be necessary but not sufficient for KSdevelopment without other cofactors. However, factors that facilitate KSHVto cause KS have not been well defined. Previously, we determined thathuman herpesvirus 6 was one of the cofactors that activated lytic cyclereplication of KSHV. Here, we demonstrate that the transactivativetranscription protein (Tat) of HIV-1 is a potentially important factor in thepathogenesis of KS, as determined by production of lytic phase mRNAtranscripts and viral proteins in BCBL-1 cells with real-time quantitativepolymerase chain reaction (Real-time PCR) and immunohistochemistryassay (IHC). Compared with control vector, the mRNA transcription level ofORF50 (switch gene of KSHV cycle replication), ORF26 (encoding KSHVminor capsid protein) and ORF29 (encoding KSHV package associatedprotein) were increased 4.33±0.49 fold (P＜0.05), 2.52±0.31 fold (P＜0.05) and 2.33±0.3 fold (P＜0.05), respectively, in Tat-transfected BCBL-1cells at 96 h. Furthermore, ORF50, ORF26 and ORF29 mRNA level in Tat-transfected BCBL-1 cells were increased 1.9 0.26 fold (P＜0.05), 1.82±0.26 fold (P＜0.05) and 1.5±0.22 fold (P＜0.05) at 120 h, respectively,compared with corresponding control. Mechanistic studies showed ectopicexpression of Tat induced the production of human interleukin-6 (huIL-6)and its receptor (huIL-6Rα) and activated STAT3 signaling. Neutralizationof huIL-6 or huIL-6Rαwith corresponding neutralizing antibody orinhibition of STAT3 signaling by JAK-2 tyrosine kinase inhibitor AG490 ordominant negative STAT3 enhanced the replication. In addition, ectopicexpression of Tat also induced the production of human interleukin-4 (IL-4)and its receptor (IL-4Rα) and activated STAT6 signaling subsequently.Inhibition of STAT6 phosphorylation with dominant negative STAT6decreased lytic replication of KSHV by Tat. These findings suggest that Tatmay participate in KS pathogenesis by inducing KSHV replication andincreasing KSHV viral load. IL-6/STAT3 and IL-4/STAT6 signalingsplayed an important role in modulation of Tat-induced KSHV relication.These data also suggest that JAK/STAT signaling may be of therapeuticvalue in AIDS-related KS patients.