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Journal of Virology, October 2006, p. 9754-9760, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.01052-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Proteasome Inhibition Reveals that a Functional Preintegration Complex Intermediate Can Be Generated during Restriction by Diverse TRIM5 Proteins

Jenny L. Anderson,1,{dagger} Edward M. Campbell,1,{dagger} Xiaolu Wu,1,2 Nick Vandegraaff,3,4 Alan Engelman,3,4 and Thomas J. Hope1,2*

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611,1 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois 60612,2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115,3 Department of Pathology, Harvard Medical School, Boston, Massachusetts 021154

Received 22 May 2006/ Accepted 8 July 2006

The primate TRIM5 proteins constitute a class of restriction factors that prevent host cell infection by retroviruses from different species. The TRIM5 proteins act early after virion entry and prevent viral reverse transcription products from accumulating. We recently found that proteasome inhibitors altered the rhesus monkey TRIM5{alpha} restriction of human immunodeficiency virus type 1 (HIV-1), allowing reverse transcription products to accumulate even though viral infection remained blocked. To assess whether sensitivity to proteasome inhibitors was a common feature of primate TRIM5 proteins, we conducted a similar analysis of restriction mediated by owl monkey TRIM-cyclophilin A (CypA) or human TRIM5{alpha}. Similar to rhesus monkey TRIM5{alpha} restriction, proteasome inhibition prevented owl monkey TRIM-CypA restriction of HIV-1 reverse transcription, even though HIV-1 infection and the output of 2-LTR circles remained impaired. Likewise, proteasome inhibition alleviated human TRIM5{alpha} restriction of N-tropic murine leukemia virus reverse transcription. Finally, HIV-1 reverse transcription products escaping rhesus TRIM5{alpha} restriction by proteasome inhibition were fully competent for integration in vitro, demonstrating that TRIM5{alpha} likely prevents the viral cDNA from accessing chromosomal target DNA. Collectively, these data indicate that the diverse TRIM5 proteins inhibit retroviral infection in multiple ways and that inhibition of reverse transcription products is not necessary for TRIM5-mediated restriction of retroviral infection.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Ward 8-140, 303 East Chicago Avenue, Chicago, IL 60611. Phone: (312) 503-1360. Fax: (312) 503-2696. E-mail: thope{at}northwestern.edu.

{dagger} These authors contributed equally to this work.

Journal of Virology, October 2006, p. 9754-9760, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.01052-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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