title: Human immunodeficiency virus type 1 induces lytic cycle replication of Kaposi's-sarcoma-associated herpesvirus: role of Ras/c-Raf/MEK1/2, PI3K/AKT, and NF-κB signaling pathways.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk and development of Kaposi's 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.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Di
authors.initials: D
authors.lastname: Qin
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lv
authors.forename: Shuihong
authors.initials: S
authors.lastname: Yao
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015497:HIV-1 / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics; D018116:Vesiculovirus / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; D018631:ras Proteins