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J. Biol. Chem., Vol. 280, Issue 29, 27284-27288, July 22, 2005

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Alanine Scanning Mutants of the HIV gp41 Loop^*

Amy Jacobs, Jayita Sen, Lijun Rong, and Michael Caffrey¶

From the Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607 and the Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612

Based on mutagenesis and structural studies of human immunodeficiency virus (HIV) envelope proteins, the loop region of gp41 is thought to directly interact with gp120. The importance of the HIV gp41 loop region to envelope function has been systematically examined by alanine scanning of all gp41 loop residues and the subsequent characterization of the mutagenic effects on viral entry, envelope expression, envelope processing, and gp120 association with gp41. With respect to the wild-type gp41, mutational effects on viral entry fall into four classes as follows: 1) little or no effect (G594A, S599A, G600A, K601A, N611A, S615A, N616A, and L619A); 2) significantly reduced entry (I595A, L602A, I603A, V608A, and K617A); 3) abolished entry (L593A, W596A, G597A, T606A, W610A, W614A, S618A, and I622A); and 4) enhanced entry (T605A, P609A, S613A, E620A, and Q621A). The reduced functionality of many mutants was apparently due to either disruption of envelope processing (L593A and T606A), viral incorporation of the envelope (W610A, W614A, and I662A), or increased dissociation of gp120 (W596A, G597A, and S618A). The extreme sensitivity of the gp120-gp41 interaction to alanine substitutions (e.g. the G597A and S618A mutants are relatively conservative substitutions) suggests that this association is an attractive and novel target for future drug discovery efforts.

Received for publication, December 22, 2004 , and in revised form, May 24, 2005.

^* This work was supported by National Institutes of Health Grant RO1 AI47674 (to M. C.). 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.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Ave, Chicago, IL 60607. Tel.: 312-996-4959; Fax: 312-413-0353; E-mail: caffrey{at}uic.edu.

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