| Title | Non-cleavage Site Gag Mutations in Amprenavir-resistant HIV-1 Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance But Delays Development of Resistance to Other Protease Inhibitors. | | Author(s) | Aoki M, Venzon DJ, Koh Y, Aoki-Ogata H, Miyakawa T, Yoshimura K, Maeda K, Mitsuya H | | Institution | Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan; Institute of Health Sciences, Kumamoto Health Science University, Kumamoto 861-5598, Japan; Biostatistics and Data Management Section, Center for Cancer Research; and Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. | | Source | J Virol 2009 Jan 28. | | Abstract | In an attempt to determine whether mutations in Gag in HIV-1 variants selected to a protease inhibitor (PI) affect the development of resistance to the same or different PI(s), we generated multiple infectious HIV-1 clones carrying mutated Gag and/or mutated protease that were identified in amprenavir (APV)-selected HIV-1 variants and examined their virological characteristics. In an HIV-1 preparation selected with APV (33 passage; HIVAPVp33), we identified 6 mutations in protease and 6 apparently critical mutations at cleavage and non-cleavage sites in Gag. An infectious recombinant clone carrying the 6 protease mutations but no Gag mutations (rHIVAPVp33pro(WTgag)) 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 5 Gag mutations (rHIVWTpro(12/75/219/390/409gag)) replicated comparably to wild-type HIV-1 (HIVWT); however, when exposed to APV, rHIVWTpro(12/75/219/390/409gag) rapidly acquired APV resistance. On the contrary, the 5 Gag mutations significantly delayed the acquisition of HIV-1 resistance to indinavir, ritonavir, and nelfinavir (NFV). Recombinant HIV-1 clones containing NFV resistance-associated mutations such as D30N and N88S had increased susceptibility to APV, suggesting that antiretroviral regimens including both APV and NFV might 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 should have clinical relevance in the therapy of HIV-1 infection with PI-including regimens. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19176623 |
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