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J. Biol. Chem., Vol. 279, Issue 42, 44141-44153, October 15, 2004

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A Late Role for the Association of hnRNP A2 with the HIV-1 hnRNP A2 Response Elements in Genomic RNA, Gag, and Vpr Localization^*

From the ^aHIV-1 RNA Trafficking Laboratory, Lady Davis Institute for Medical Research-Sir Mortimer B. Davis Jewish General Hospital, Room 323A, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada, the Departments of ^bMicrobiology & Immunology and ^kMedicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 2B4, Canada, the ^dDépartement de Microbiologie et infectiologie, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, the ^fDépartement de Microbiologie et immunologie, Université de Montréal, Montréal, Québec H3G 1J4, Canada, the ⁱDepartment of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the ^jDepartments of Medicine, Microbiology & Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756

Two cis-acting RNA trafficking sequences (heterogenous ribonucleoprotein A2 (hnRNP A2)-response elements 1 and 2 or A2RE-1 and A2RE-2) have been identified in HIV-1 vpr and gag mRNAs and were found to confer cytoplasmic RNA trafficking in a murine oligodendrocyte assay. Their activities were assessed during HIV-1 proviral gene expression in COS7 cells. Single point mutations that were shown to severely block RNA trafficking were introduced into each of the A2REs. In both cases, this resulted in a marked decrease in hnRNP A2 binding to HIV-1 genomic RNA in whole cell extracts and hnRNP A2-containing polysomes. This also resulted in an accumulation of HIV-1 genomic RNA in the nucleus and a significant reduction in genomic RNA encapsidation levels. Immunofluorescence analyses revealed altered expression patterns for pr55^Gag and particularly that for Vpr. Vpr localization became almost completely nuclear and this was reflected in a significant reduction in virion-associated Vpr levels. These effects coincided with late steps of the viral replication cycle and were not seen at early time points post-transfection. Transcription, splicing, steady state RNA levels, and pr55^Gag processing were not affected. On the other hand, viral replication was markedly compromised in A2RE-2 mutant viruses and this correlated with lowered genomic RNA encapsidation levels. These data reveal new insights into the virus-host interactions between hnRNP A2 and the HIV-1 A2REs and their influence on the patterns of HIV-1 gene expression and viral assembly.

Received for publication, April 27, 2004 , and in revised form, July 22, 2004.

^* This work was supported by grants from the Canadian Foundation for AIDS Research (to A. J. M.), the Canadian Foundation for Innovation (to A. J. M.), and grants from the Canadian Institutes of Health Research (CIHR) (to A. J. M., A. W. C., B. C., and É. A. C.) and a National Institutes of Health Grant (to W. F. C. R). 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 Supplementary Materials.

^c Supported by studentships from the Fondation Georges-Phenix and Fonds pour la recherche en santé du Québec (FRSQ).

^e Supported by a studentship from the Natural Sciences and Engineering Research Council of Canada.

^g Recipient of a Canada Research Chair in Functional Genomics.

^h Recipients of a Canada Research Chair in Retrovirology.

^l A Scholar of the FRSQ and the recipient of a New Investigator Award from the CIHR. To whom correspondence should be addressed. Tel.: 514-340-8260; Fax: 514-340-7537; E-mail: andrew.mouland{at}mcgill.ca.

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