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Journal of Virology, July 2006, p. 7186-7198, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.02084-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Involvement of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in the Regulation of Resistance to Nucleoside Inhibitors

Valentina Svicher,1,{dagger} Tobias Sing,2,{dagger} Maria Mercedes Santoro,1 Federica Forbici,3 Fátima Rodríguez-Barrios,4 Ada Bertoli,1 Niko Beerenwinkel,2,{ddagger} Maria Concetta Bellocchi,3 Federigo Gago,4 Antonella d'Arminio Monforte,5,§ Andrea Antinori,3 Thomas Lengauer,2 Francesca Ceccherini-Silberstein,1* and Carlo Federico Perno1,3

Department of Experimental Medicine, University of Rome Tor Vergata, Rome,1 National Institute for Infectious Diseases L. Spallanzani, Rome,3 Institute of Infectious and Tropical Diseases, University of Milan, Milan, Italy,5 Max Planck Institute for Informatics, Saarbrücken, Germany,2 Department of Pharmacology, University of Alcalá, Alcalá de Henares, Spain4

Received 4 October 2005/ Accepted 14 April 2006

We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naïve patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L+L210W+T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N+K70R+K219Q+T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response 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 T.S. contributed equally to this work.

{ddagger} Present address: University of California, Berkeley, Calif.

§ For the ICONA study group.

Journal of Virology, July 2006, p. 7186-7198, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.02084-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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