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Journal of Virology, March 2007, p. 2401-2417, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.02024-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Intracellular Tat of Human Immunodeficiency Virus Type 1 Activates Lytic Cycle Replication of Kaposi's Sarcoma-Associated Herpesvirus: Role of JAK/STAT Signaling{triangledown}

Yi Zeng,1,2,3,4,{dagger} Xunhai Zhang,5,{dagger} Zan Huang,6,{dagger} Lin Cheng,3 Shuihong Yao,3 Di Qin,3 Xiuying Chen,3 Qiao Tang,3 Zhigang Lv,3 Ling Zhang,3 and Chun Lu1,2,3*

Laboratory of Reproductive Medicine,1 Jiangsu Province Laboratory of Pathogen Biology,2 Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, People's Republic of China,3 Department of Microbiology and Immunology, Youjiang Medical College for Nationalities, Bose 533000, People's Republic of China,4 College of Animal Science, Anhui Science and Technology University, Fengyang 233100, People's Republic of China,5 Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 606376

Received 15 September 2006/ Accepted 25 November 2006

Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk of Kaposi's sarcoma (KS) occurrence in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV infection appears to be necessary but not sufficient for KS development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we determined that human herpesvirus 6 was one of the cofactors that activated lytic cycle replication of KSHV. Here, we demonstrate that the Tat protein of HIV-1 is a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts and viral proteins in BCBL-1 cells. Mechanistic studies showed ectopic expression of Tat induced the production of human interleukin-6 (huIL-6) and its receptor (huIL-6Ra) and activated STAT3 signaling. Neutralization of huIL-6 or huIL-6R or inhibition of STAT3 signaling enhanced the replication. In addition, IL-4/STAT6 signaling also partially contributed to Tat-induced KSHV replication. These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, People's Republic of China. Phone: 86-25-86862910. Fax: 86-25-86508960. E-mail: clu{at}njmu.edu.cn.

{triangledown} Published ahead of print on 6 December 2006.

{dagger} Y.Z., X.Z., and Z.H. contributed equally to this work.

Journal of Virology, March 2007, p. 2401-2417, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.02024-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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