Human Immunodeficiency Virus Type 1 Induces Lytic Cycle Replication of Kaposiʹs-Sarcoma-Associated Herpesvirus: Role of Ras/c-Raf/MEK1/2, PI3K/AKT, and NF-κB Signaling Pathways

Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk and development of Kaposiʹs sarcoma (KS) in individuals infected with KS-associated herpesvirus (KSHV). Previously, we reported that HIV-1 Tat protein induced KSHV replication by modulating the Janus kinase/signal transducers and activators of transcription signaling pathway. Here, we further investigated the possible signaling pathways involved in HIV-1-induced reactivation of KSHV. We showed that HIV-1 infection of primary effusion lymphoma cell lines triggered the reactivation of KSHV, as demonstrated by the expression of KSHV replication and transcription activator, the early viral lytic protein vIL-6 and ORF59 and the production of progeny virions. By utilizing microarray gene expression analyses, transfecting a series of dominant negative mutants, and adding pharmacologic inhibitors, we identified a group of diverse cellular signaling proteins and found that HIV-1 infection of BCBL-1 cells activated phosphatidylinositol 3-kinase/AKT (also called protein kinase B, PKB) pathway and inactivated phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase-3β, which partially modulated HIV-1-induced KSHV reactivation. Furthermore, activation of Ras/c-Raf/MAPK/ERK kinase1/2 pathway contributed to HIV-1-induced KSHV replication. Finally, we discovered that HIV-1 infection activated nuclear factor κB signaling, which exhibits an inhibitory effect on KSHV reactivation in BCBL-1 cells. Collectively, our data demonstrated that HIV-1 infection stimulated these cell signaling pathways that, in turn, contributed to KSHV reactivation, which may be of therapeutic value in acquired immunodeficiency syndrome-related KS patients.