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J. Biol. Chem., Vol. 279, Issue 34, 35923-35931, August 20, 2004

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Structural Variability of the Initiation Complex of HIV-1 Reverse Transcription^*

Valérie Goldschmidt, Jean-Christophe Paillart, Mickaël Rigourd, Bernard Ehresmann, Anne-Marie Aubertin¶, Chantal Ehresmann, and Roland Marquet||

From the Unité Propre de Recherche 9002 du CNRS conventionnée à l'Université Louis Pasteur, IBMC, 15 rue René Descartes, 67084 Strasbourg cedex, France and the ^¶Institut de Virologie, UMR544 INSERM-Université Louis Pasteur, 67000 Strasbourg, France

HIV-1 reverse transcription is initiated from a molecule annealed to the viral RNA at the primer binding site (PBS), but the structure of the initiation complex of reverse transcription remains controversial. Here, we performed in situ structural probing, as well as in vitro structural and functional studies, of the initiation complexes formed by highly divergent isolates (MAL and NL4.3/HXB2). Our results show that the structure of the initiation complex is not conserved. In MAL, and according to sequence analysis in 14% of HIV-1 isolates, formation of the initiation complex is accompanied by complex rearrangements of the viral RNA, and extensive interactions with are required for efficient initiation of reverse transcription. In NL4.3, HXB2, and most isolates, annealing minimally affects the viral RNA structure and no interaction outside the PBS is required for optimal initiation of reverse transcription. We suggest that in MAL, extensive interactions with are required to drive the structural rearrangements generating the structural elements ultimately recognized by reverse transcriptase. In NL4.3 and HXB2, these elements are already present in the viral RNA prior to annealing, thus explaining that extensive interactions with the primer are not required. Interestingly, such interactions are required in HXB2 mutants designed to use a non-cognate tRNA as primer (tRNA^His). In the latter case, the extended interactions are required to counteract a negative contribution associate with the alternate primer.

Received for publication, April 22, 2004 , and in revised form, June 10, 2004.

^* This work was supported by grants from the Agence Nationale de Recherches sur le SIDA (ANRS) (to C. E. and R. M.). 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.

Present address: Dept. of Genetics and Microbiology, Faculty of Medicine, University of Geneva, Switzerland.

^|| To whom correspondence should be addressed. Tel.: 33-3-88-41-70-35; Fax: 33-3-88-60-22-18; E-mail: r.marquet{at}ibmc.u-strasbg.fr.

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