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Journal of Virology, April 2009, p. 3059-3068, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02539-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors{triangledown}

Manabu Aoki,1,2 David J. Venzon,3 Yasuhiro Koh,1 Hiromi Aoki-Ogata,1 Toshikazu Miyakawa,1 Kazuhisa Yoshimura,1 Kenji Maeda,1,4 and Hiroaki Mitsuya1,4*

Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan,1 Institute of Health Sciences, Kumamoto Health Science University, Kumamoto 861-5598, Japan,2 Biostatistics and Data Management Section,3 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208924

Received 10 December 2008/ Accepted 20 January 2009

In an attempt to determine whether mutations in Gag in human immunodeficiency virus type 1 (HIV-1) variants selected with a protease inhibitor (PI) affect the development of resistance to the same or a different PI(s), we generated multiple infectious HIV-1 clones carrying mutated Gag and/or mutated protease proteins that were identified in amprenavir (APV)-selected HIV-1 variants and examined their virological characteristics. In an HIV-1 preparation selected with APV (33 passages, yielding HIVAPVp33), we identified six mutations in protease and six apparently critical mutations at cleavage and non-cleavage sites in Gag. An infectious recombinant clone carrying the six protease mutations but no Gag mutations failed to replicate, indicating that the Gag mutations were required for the replication of HIVAPVp33. An infectious recombinant clone that carried wild-type protease and a set of five Gag mutations (rHIVWTpro12/75/219/390/409gag) replicated comparably to wild-type HIV-1; however, when exposed to APV, rHIVWTpro12/75/219/390/409gag rapidly acquired APV resistance. In contrast, the five Gag mutations significantly delayed the acquisition of HIV-1 resistance to ritonavir and nelfinavir (NFV). Recombinant HIV-1 clones containing NFV resistance-associated mutations, such as D30N and N88S, had increased susceptibilities to APV, suggesting that antiretroviral regimens including both APV and NFV may bring about favorable antiviral efficacy. The present data suggest that the preexistence of certain Gag mutations related to PI resistance can accelerate the emergence of resistance to the PI and delay the acquisition of HIV resistance to other PIs, and these findings should have clinical relevance in the therapy of HIV-1 infection with PI-including regimens.

* Corresponding author. Mailing address: Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: (81) 96-373-5156. Fax: (81) 96-363-5265. E-mail: hm21q{at}nih.gov

{triangledown} Published ahead of print on 28 January 2009.

Journal of Virology, April 2009, p. 3059-3068, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02539-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Banke, S., Lillemark, M. R., Gerstoft, J., Obel, N., Jorgensen, L. B. (2009). Positive Selection Pressure Introduces Secondary Mutations at Gag Cleavage Sites in Human Immunodeficiency Virus Type 1 Harboring Major Protease Resistance Mutations. J. Virol. 83: 8916-8924 [Abstract] [Full Text]  


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