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J. Biol. Chem., Vol. 281, Issue 42, 31348-31358, October 20, 2006

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SerpinB2 Is an Inducible Host Factor Involved in Enhancing HIV-1 Transcription and Replication^*

Grant A. Darnell, Wayne A. Schroder, Joy Gardner, David Harrich, Hong Yu, Robert L. Medcalf, David Warrilow, Toni M. Antalis^¶, Secondo Sonza^||, and Andreas Suhrbier¹

From the Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia, the Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3800, Australia, the ^¶Department of Physiology, University of Maryland School of Medicine, Rockville, Maryland 20854, and the ^||AIDS Pathogenesis Research, Macfarlane Burnet Centre for Medical Research, Melbourne, Victoria 3001, Australia

The serine protease inhibitor SerpinB2 (plasminogen activator inhibitor-2) is a major product of activated monocytes and macrophages and is substantially induced during most inflammatory processes. Distinct from its widely described extracellular role as an inhibitor of urokinase plasminogen activator, SerpinB2 has recently been shown to have an intracellular role as a retinoblastoma protein (Rb)-binding protein that inhibits Rb degradation. Here we show that HIV-1 infection and gp120 treatment of human peripheral blood mononuclear cells resulted in induction of SerpinB2. Furthermore, SerpinB2 expression in THP-1 monocyte/macrophage, Jurkat T, and HeLa cell lines increased replication of HIV-1 and enhanced transcription from the HIV-1 long terminal repeat (LTR) promoter by 3–10-fold. Increased HIV-1 gene expression and transcription was also observed in activated macrophages from SerpinB2^+/+ mice compared with macrophages from SerpinB2^–/– mice. The SerpinB2-mediated elevation of Rb protein levels appeared to be responsible for enhancing transcription from the core promoter region of the LTR by relieving HDM2-mediated inhibition of Sp1 and/or by increasing the Sp1/Sp3 expression ratios. This is the first report associating HIV-1 replication with SerpinB2 expression and illustrates that SerpinB2 is a potentially important inducible host factor that significantly promotes HIV-1 replication.

Received for publication, May 3, 2006 , and in revised form, August 7, 2006.

^* This work was supported in part by the National Health and Medical Research Council of Australia and the National Institutes of Health (R01-CA098369 [GenBank] ). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6 and Table S1.

¹ To whom correspondence should be addressed: Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Queensland 4029, Australia. Tel.: 61-7-33620415; Fax: 61-7-33620107; E-mail: Andreas.Suhrbier{at}qimr.edu.au.

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