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RESEARCH PAPER

hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region

University of Massachusetts Medical School, Program in Molecular Medicine and the UMASS Center for AIDS Research (CFAR), Worcester, Massachusetts 01605, USA

Human immunodeficiency virus Rev facilitates the cytoplasmic accumulation of viral RNAs that contain a Rev binding site. A human Rev-interacting protein (hRIP) was originally identified based on its ability to interact with the Rev nuclear export signal (NES) in yeast two-hybrid assays. To date, however, the function of hRIP and a role for hRIP in Rev-directed RNA export have remained elusive. Here we ablate hRIP activity with a dominant-negative mutant or RNA interference and analyze Rev function by RNA in situ hybridization. We find, unexpectedly, that in the absence of functional hRIP, Rev-directed RNAs mislocalize and aberrantly accumulate at the nuclear periphery, where hRIP is localized. In contrast, in the absence of Rev or the Rev cofactor CRM1, Rev-directed RNAs remain nuclear. We further show that the RNA mislocalization pattern resulting from loss of hRIP activity is highly specific to Rev function: the intracellular distribution of cellular poly(A)⁺ mRNA, nuclear proteins, and, most important, NES-containing proteins, are unaffected. Thus, hRIP is an essential cellular Rev cofactor, which acts at a previously unanticipated step in HIV-1 RNA export: movement of RNAs from the nuclear periphery to the cytoplasm.

[Keywords: Rev; HIV-1; RNA export; hRIP]

Received September 3, 2003; revised version accepted November 10, 2003.

¹ Corresponding author.

E-MAIL Maria.Zapp{at}umassmed.edu; FAX (508) 856-4588.

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