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Journal of Virology, October 2002, p. 9724-9734, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9724-9734.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 (HIV-1) Accessory Protein Vpr Induces Transcription of the HIV-1 and Glucocorticoid-Responsive Promoters by Binding Directly to p300/CBP Coactivators

Tomoshige Kino,1* Alexander Gragerov,2 Olga Slobodskaya,2 Maria Tsopanomichalou,2 George P. Chrousos,1 and George N. Pavlakis2*

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1583,1 Human Retrovirus Section, Center for Cancer Research, National Cancer Institute—Frederick, Frederick, Maryland 21702-12012

Received 7 March 2002/ Accepted 15 June 2002

The accessory Vpr protein of human immunodeficiency virus type 1 (HIV-1) is a promiscuous activator of viral and cellular promoters. We report that Vpr enhances expression of the glucocorticoid receptor-induced mouse mammary tumor virus (MMTV) promoter and of the Tat-induced HIV-1 long terminal repeat promoter by directly binding to p300/CBP coactivators. In contrast, Vpr does not bind to p/CAF or to members of the p160 family of nuclear receptor coactivators, such as steroid receptor coactivator 1a and glucocorticoid receptor (GR)-interacting protein 1. Vpr forms a stable complex with p300 and also interacts with the ligand-bound glucocorticoid receptor in vivo. Mutation analysis showed that the C-terminal part of Vpr binds to the C-terminal portion of p300/CBP within amino acids 2045 to 2191. The same p300 region interacts with the p160 coactivators and with the adenovirus E1A protein. Accordingly, E1A competed for binding to p300 in vitro. Coexpression of E1A or of small fragments of p300 containing the Vpr binding site resulted in inhibition of Vpr's transcriptional effects. The C-terminal part of p300 containing the transactivating region is required for Vpr transactivation, whereas the histone acetyltransferase enzymatic region is dispensable. Vpr mutants that bind p300 but not the GR did not activate expression of the MMTV promoter and had dominant-negative effects. These results indicate that Vpr activates transcription by acting as an adapter linking transcription components and coactivators.

* Corresponding author. Mailing address for Tomoshige Kino: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, Rm. 9D42, 10 Center Dr., MSC 1583, Bethesda, MD 20892-1583. Phone: (301) 496-6417. Fax: (301) 480-2024. E-mail: kinot{at}mail.nih.gov.

* Corresponding author. Mailing address for George N. Pavlakis: Human Retrovirus Section, Center for Cancer Research, National Cancer Institute-—Frederick, Bldg. 535, Rm. 210, Frederick, MD 21702-1201. Phone: (301) 846-1474. Fax: (301) 846-6368. E-mail: pavlakis{at}ncifcrf.gov.

Journal of Virology, October 2002, p. 9724-9734, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9724-9734.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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