alexa Drug Resistance Pathways and Impact of Protease Mutation L10I/V in HIV-1 Non-B Subtypes | OMICS International | Abstract
ISSN: 1948-5964

Journal of Antivirals & Antiretrovirals
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Research Article

Drug Resistance Pathways and Impact of Protease Mutation L10I/V in HIV-1 Non-B Subtypes

Alpha Haidara1, Annie Chamberland1,2, Mohamed Sylla2, Souleymane Ag Aboubacrine3, Mamadou Cissé4, Hamar A. Traore3, Moussa Y. Maiga5, Anatole Tounkara3, Vinh Kim Nguyen1 and Cécile L. Tremblay1,2*

1Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Canada

2Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Canada

3Hôpital national du Point-G, Bamako, Mali

4CÉSAC, Bamako, Mali

5Hôpital Gabriel Touré, Bamako, Mali

*Corresponding Author:
Cécile Tremblay,M.D., FRCPC
Centre Hospitalier del’Université de Montréal
3840 rue St-Urbain, Bureau 7-355
Montréal (Qc) H2W 1T8,Canada
Tel : 514-890-8000
Fax: 514-412-7234
E-mail: [email protected]

Received Date: March 12, 2012; Accepted Date: April 26, 2012; Published Date: April 27, 2012

Citation: Haidara A, Chamberland A, Sylla M, Aboubacrine SA, Cissé M, et al. (2012) Drug Resistance Pathways and Impact of Protease Mutation L10I/V in HIV- 1 Non-B Subtypes. J Antivir Antiretrovir 4: 043-050. doi: 10.4172/jaa.1000045

Copyright: © 2012 Haidara A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Molecular pathways to drug resistance have yet to be fully characterized in HIV-1 non-B subtypes. Furthermore, polymorphisms such as protease L10I/V are ubiquitous in non-B subtypes, but their biological implications are still unknown. We evaluated resistance pathways emerging at treatment failure in a cohort of HIV infected individuals in Mali, and characterized in vitro the role of L10I/V.
Methods: Genotypic resistance testing was performed on plasma obtained from 132 HIV-infected individuals from Mali before and after 9 months of treatment using population sequencing. CRF02_AG chimeric viruses containing 10I/V mutants CRF02_AG were constructed using site directed mutagenesis and susceptibility to protease inhibitors (PI) as well as replicative capacity were determined in a PBMC culture assay.
Results: At treatment initiation, 11/132 (8.3%; 95% CI 3.6-13.0%) patients harboured resistance mutations to NRTI (D67N, T69N, L210W, K219E and T215A) or NNRTI (K103N, V108I and V179E). Among these 11 patients, 5 with NNRTI mutations were in virological failure after 9 months of treatment. Six others with one Thymidine Analog Mutations (TAM) did not show complete resistance. Overall, 18/132 (14.0%; 95% CI 8.1-19.9%) patients failed at 9 months and resistance mutations to NRTI or NNRTI could be identified in 8 (6.10%; 95% CI 2.0-10.2%). NRTI mutation M184V was the most commonly observed, followed by NNRTI mutations Y181C and K103N. Polymorphisms in protease such as L10I/V were observed frequently. Their role was evaluated in vitro. CRF02_AGwt_10L showed a slight increase in IC50 for darunavir, lopinavir and nelfinavir compared to subtype BHXB2_10L with 1.2, 1.3 and 1.5 Fold-Changes (FC) respectively. Mutant’s viruses CRF02_AGL10I and CRF02_AGL10V showed a slight increase in IC50 for indinavir with 1.30 and 1.20 FC and a slight decrease in IC50 for lopinavir with 0.78 FC and 0.75 FC respectively compared to CRF02_AGwt_10L. We did not observe any difference in replicative capacity between CRF02_AGwt_10L and HXB2. However, compared to CRF02_AGwt_10L, mutants, viruses CRF02_AGL10I, and CRF02_AGL10V showed a significant reduction in replication capacity by 10% (p<0.03) and 12% (p<0.02) respectively.
Conclusion: Primary resistance to NRTI and NNRTI impacts response to treatment. The presence of a single TAM mutation may have limited impact on first line treatment in CRF02_AG. A common polymorphism in non-B subtypes, L10V, may affect susceptibility of certain PIs. In the context of large-scale use of antiretroviral, monitoring the emergence of resistance in non-B subtypes is important to preserve treatment options.

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