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Journal of Virology, October 2007, p. 11507-11519, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00303-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Characterization and Structural Analysis of Novel Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involved in the Regulation of Resistance to Nonnucleoside Inhibitors

Francesca Ceccherini-Silberstein,^1,* Valentina Svicher,^1, Tobias Sing,² Anna Artese,^3,4 Maria Mercedes Santoro,¹ Federica Forbici,⁵ Ada Bertoli,¹ Stefano Alcaro,^3,4 Guido Palamara,⁶ Antonella d'Arminio Monforte ,^7, Jan Balzarini,⁸ Andrea Antinori ,^5, Thomas Lengauer,² and Carlo Federico Perno^1,5,

Department of Experimental Medicine, University of Rome Tor Vergata, Rome,¹ Department of Pharmacobiological Sciences, University of Catanzaro Magna Graecia, Roccelletta di Borgia (CZ),³ National Institute of Nuclear Physics, Frascati, Rome,⁴ National Institute for Infectious Diseases L. Spallanzani, Rome,⁵ San Gallicano Hospital, Rome,⁶ Institute of Infectious and Tropical Diseases, University of Milan, Milan, Italy,⁷ Max-Planck-Institute for Informatics, Saarbrücken, Germany,² Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium⁸

Received 12 February 2007/ Accepted 2 August 2007

Resistance to antivirals is a complex and dynamic phenomenon that involves more mutations than are currently known. Here, we characterize 10 additional mutations (L74V, K101Q, I135M/T, V179I, H221Y, K223E/Q, and L228H/R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase which are involved in the regulation of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). These mutations are strongly associated with NNRTI failure and strongly correlate with the classical NNRTI resistance mutations in a data set of 1,904 HIV-1 B-subtype pol sequences from 758 drug-naïve patients, 592 nucleoside reverse transcriptase inhibitor (NRTI)-treated but NNRTI-naïve patients, and 554 patients treated with both NRTIs and NNRTIs. In particular, L74V and H221Y, positively correlated with Y181C, were associated with an increase in Y181C-mediated resistance to nevirapine, while I135M/T mutations, positively correlated with K103N, were associated with an increase in K103N-mediated resistance to efavirenz. In addition, the presence of the I135T polymorphism in NNRTI-naïve patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular dynamics simulations show that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y. H221Y also showed negative correlations with type 2 thymidine analogue mutations (TAM2s); its copresence with the TAM2s was associated with a higher level of zidovudine susceptibility. Our study reinforces the complexity of NNRTI resistance and the significant interplay between NRTI- and NNRTI-selected mutations. Mutations beyond those currently known to confer resistance should be considered for a better prediction of clinical response to reverse transcriptase inhibitors and for the development of more efficient new-generation NNRTIs.

Published ahead of print on 8 August 2007.

F.C.-S. and V.S. contributed equally to this work.

For the I.Co.N.A. Study Group (see Acknowledgments for a list of the members of this study group).

For the INMI-Collaborative Group for Clinical Use of HIV Genotype Resistance Test (see Acknowledgments for a list of the members of this study group).