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: Xiaolei Zhu, Feng Zhou, Di Qin, Yi Zeng, Zhigang Lv, Shuihong Yao, Chun Lu
• Journal: Journal of molecular biology (J Mol Biol) Vol. 410 Issue 5 Pg. 1035-51 (Jul 29 2011) ISSN: 1089-8638 [Electronic] Netherlands
• PMID: 21763505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• NF-kappa B
• Phosphatidylinositol 3-Kinases
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-raf
• Glycogen Synthase Kinase 3
• Mitogen-Activated Protein Kinase Kinases
• PTEN Phosphohydrolase
• ras Proteins

Topics

• Animals
• Cell Line
• Enzyme Activation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• HIV-1 (physiology)
• Herpesvirus 8, Human (physiology)
• Humans
• Mice
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• NF-kappa B (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Signal Transduction
• Up-Regulation (genetics)
• Vesiculovirus (physiology)
• Virus Replication (physiology)
• ras Proteins (metabolism)