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J. Biol. Chem., Vol. 283, Issue 24, 16723-16731, June 13, 2008

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Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

INTERACTION WITH gp41 FUSION CORE^*

Lu Lu¹, Yun Zhu¹, Jinghe Huang, Xi Chen, Hengwen Yang, Shibo Jiang², and Ying-Hua Chen³

From the Laboratory of Immunology, Department of Biology, Tsinghua University, Beijing Key Laboratory for Protein Therapeutics, Beijing 100084, China and Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10065

HIV-1 gp41 cytoplasmic tail (CT) is highly conserved among HIV-1 isolates, particularly the region designated lentivirus lytic peptide (LLP1–2), which includes two -helical domains LLP1 and LLP2. Although the gp41 CT is recognized as a modulator of viral fusogenicity, little is known about the regulatory mechanism of this region in the viral fusion process. Here we report that anti-LLP1–2 and anti-LLP2 antibodies (IgG) inhibited HIV-1 Env-mediated cell fusion and bound to the interface between effector and target cells at a suboptimal temperature (31.5 °C), which slows down the fusion process and prolongs the fusion intermediate state. This suggests that LLP1–2, especially the LLP2 region located inside the viral membrane, is transiently exposed on the membrane surface during the fusion process. Synthetic LLP2 peptide could bind to the gp41 six-helix bundle core with high binding affinity. These results suggest that the gp41 CT may interact with the gp41 core, via the surface-exposed LLP2 domain, to regulate Env-mediated membrane fusion.

Received for publication, February 11, 2008 , and in revised form, April 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AI46221. This work was also supported by the Emphases Project of NSFC-30530680 and 973-2006CB504203 (to Y. H. C.) and the Outstanding Overseas Chinese Scholars Fund of Chinese Academy of Sciences Grant 2005-2-6 (to S. J.). 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.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 212-570-3058; Fax: 212-570-3099; E-mail: sjiang{at}nybloodcenter.org. ³ To whom correspondence may be addressed. Tel.: 86-10-6277-2267; Fax: 86-10-6277-1613; E-mail: chenyh{at}mail.tsinghua.edu.cn.

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