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Antimicrobial Agents and Chemotherapy, May 2005, p. 2015-2025, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.2015-2025.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors

Valentina Svicher,1,{dagger} Francesca Ceccherini-Silberstein,1,{dagger}* Fulvio Erba,1 Maria Santoro,1 Caterina Gori,2 Maria Concetta Bellocchi,2 Sara Giannella,2 Maria Paola Trotta,2 Antonella d'Arminio Monforte,3 Andrea Antinori,2 and Carlo Federico Perno2

Department of Experimental Medicine, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome,1 National Institute for Infectious Diseases "L. Spallanzani," Via Portuense 292, 00149 Rome,2 Institute of Infectious and Tropical Diseases, University of Milan, Hospital Sacco, Via G. B. Grassi 74, 20157 Milan, Italy3

Received 6 August 2004/ Returned for modification 12 October 2004/ Accepted 3 January 2005

Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naïve patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 Å of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naïve patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs.

* Corresponding author. Mailing address: Department of Experimental Medicine, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy. Phone: 39-06-72596553. Fax: 39-06-72596039. E-mail: ceccherini{at}med.uniroma2.it.

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

Antimicrobial Agents and Chemotherapy, May 2005, p. 2015-2025, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.2015-2025.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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