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Journal of Virology, January 2006, p. 130-137, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.130-137.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

"UnPAKing" Human Immunodeficiency Virus (HIV) Replication: Using Small Interfering RNA Screening To Identify Novel Cofactors and Elucidate the Role of Group I PAKs in HIV Infection

Deborah G. Nguyen,* Karen C. Wolff, Hong Yin, Jeremy S. Caldwell,{dagger} and Kelli L. Kuhen{dagger}

Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121

Received 1 June 2005/ Accepted 4 October 2005

In order to identify novel proviral host factors involved in human immunodeficiency virus (HIV) infection, we performed a screen of a small interfering RNA (siRNA) library targeting 5,000 genes with the highest potential for being targets for therapeutics. Many siRNAs in the library against known host factors, such as TSG101, furin, and CXCR4, were identified as inhibitors by the screen and thus served as internal validation. In addition, many novel factors whose knockdown inhibited infection were identified, including Pak3, a member of the serine/threonine group I PAK kinases. The HIV accessory factor Nef has been shown to associate with a PAK kinase, leading to enhanced viral production; however, the exact identity of the kinase has remained controversial. Prompted by the Pak3 screen hit, we further investigated the involvement of group I PAK kinases in HIV using siRNA. Contrary to the current literature, Pak1 depletion strongly inhibited HIV infection in multiple cell systems and decreased levels of integrated provirus, while Pak2 depletion showed no effect. Overexpression of a constitutively active Pak1 mutant also enhanced HIV infection, further supporting its role as the dominant PAK involved.

* Corresponding author. Mailing address: 10675 John Jay Hopkins Dr., San Diego, CA 92121. Phone: (858) 332-4705. Fax: (858) 812-1597. E-mail: deborah.nguyen{at}gnf.org.

{dagger} J.S.C. and K.L.K. contributed equally to this work.

Journal of Virology, January 2006, p. 130-137, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.130-137.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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