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Antimicrobial Agents and Chemotherapy, February 2009, p. 708-715, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01109-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2 {triangledown} ,{dagger}

Michel L. Ntemgwa,1,2 Thomas d'Aquin Toni,1 Bluma G. Brenner,1 Maureen Oliveira,1 Eugene L. Asahchop,1 Daniela Moisi,1 and Mark A. Wainberg1,2*

McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada,1 Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada2

Received 18 August 2008/ Returned for modification 2 October 2008/ Accepted 29 November 2008

Recent findings suggest bidirectional antagonisms between the K65R mutation and thymidine analogue mutations in human immunodeficiency virus type 1 (HIV-1)-infected, treatment-experienced patients, yet little is known about HIV-2 in this regard. This study addressed the effects of innate polymorphisms in HIV-2 on emergent resistance to nucleoside/nucleotide analogues. Emergent drug resistance profiles in HIV-2 subtypes A (n = 3) and B (n = 1) were compared to those of HIV-1 subtypes B and C. Drug resistance was evaluated with cord blood mononuclear cells (CBMCs) and MT2 cells, using selective pressure with tenofovir (TFV), zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), or various dual-drug combinations. Resistance was evaluated using conventional and ultrasensitive sequencing approaches. In agreement with our previous findings, dual-drug combinations of TFV, ddI, ABC, d4T, ZDV, and 3TC preferentially selected for K65R in HIV-1 subtype C isolates. In HIV-1 subtype B, TFV-3TC and ZDV-3TC selected for M184I and D67N, respectively. In contrast, selections with all four HIV-2 cultures favored the development of M184I in dual-drug combinations that included either 3TC or FTC. Since HIV-2 cultures did not develop K65R, an ultrasensitive allele-specific real-time PCR assay was developed to distinguish the presence of 65R from wild-type K65 after 16 cycles with a discriminatory ability of 0.1% against a population of wild-type virus. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and show that polymorphisms may influence the development of the resistance pathways that are likely to emerge.

* Corresponding author. Mailing address: McGill AIDS Centre, Jewish General Hospital, 3755 Cote Ste. Catherine Rd., Montreal, Quebec, Canada H3T 1E2. Phone: (514) 340-8260. Fax: (514) 340-7537. E-mail: mark.wainberg{at}mcgill.ca

{triangledown} Published ahead of print on 8 December 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, February 2009, p. 708-715, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01109-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ntemgwa, M. L., Toni, T. d., Brenner, B. G., Camacho, R. J., Wainberg, M. A. (2009). Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2. Antimicrob. Agents Chemother. 53: 3611-3619 [Full Text]  


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