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J Virol, February 1998, p. 986-993, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides

Laurence T. Rimsky, Diane C. Shugars,dagger and Thomas J. Matthews*

Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710

Received 3 July 1997/Accepted 22 October 1997

A synthetic peptide, DP178, containing amino acids 127 to 162 of the human immunodeficiency virus type 1 (HIV-1) gp41 Env glycoprotein, is a potent inhibitor of virus infection and virus mediated cell-to-cell fusion (C. Wild, T. Greenwell, and T. Matthews, AIDS Res. Hum. Retroviruses 9:1051-1053, 1993). In an effort to understand the mechanism of action of this peptide, we derived resistant variants of HIV-1IIIB and NL4-3 by serial virus passage in the presence of increasing doses of the peptide. Sequence analysis of the resistant isolates suggested that a contiguous 3-amino-acid sequence within the amino-terminal heptad repeat motif of gp41 was associated with resistance. Site-directed mutagenesis studies confirmed this observation and indicated that changes in two of these three residues were necessary for development of the resistant phenotype. Direct binding of DP178 to recombinant protein and synthetic peptide analogs containing the wild-type and mutant heptad repeat sequences revealed a strong correlation between DP178 binding and the biological sensitivity of the corresponding virus isolates to DP178. The results are discussed from the standpoints of the mechanism of action of DP178 and recent crystallographic information for a core structure of the gp41 ectodomain.

* Corresponding author. Mailing address: Center for AIDS Research, P.O. Box 2926, Department of Surgery, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-4215. Fax: (919) 684-4288. E-mail: matth006{at}mc.duke.edu.

dagger Present address: Department of Dental Ecology and Microbiology/Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7456.




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Copyright © 1998 by the American Society for Microbiology. All rights reserved.