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Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors

  1. Author:
    Gatanaga, H.
    Suzuki, Y.
    Tsang, H.
    Yoshimura, K.
    Kavlick, M. F.
    Nagashima, K.
    Gorelick, R. J.
    Mardy, S.
    Tang, C.
    Summers, M. F.
    Mitsuya, H.

  2. Author Address

    NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, NIH, Bldg 10, Rm 5A11, 9000 Rockville Pike, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. NCI, Sci Applicat Int Corp, AIDS Vaccine Program, Frederick, MD 21701 USA. NCI, Sci Applicat Int Corp, Image Anal Lab, Frederick, MD 21701 USA. Univ Maryland, Howard Hughes Med Inst, Baltimore, MD 21250 USA. Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA. Mitsuya H NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, NIH, Bldg 10, Rm 5A11, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    1. Year: 2002
  2. Journal: Journal of Biological Chemistry
    1. 277
    2. 8
    3. Pages: 5952-5961
  4. Type of Article: Article
  1. Abstract:

    Amino acid substitutions in human immunodeficiency virus type 1 (HIV-1) Gag cleavage sites have been identified in HIV-1 isolated from patients with AIDS failing chemotherapy containing protease inhibitors (PIs). However, a number of highly PI-resistant HIV-1 variants lack cleavage site amino acid substitutions. In this study we identified multiple novel amino acid substitutions including L75R, H219Q V390D/V390A, R409K, and E468K in the Gag protein at non-cleavage sites in common among HIV-1 variants selected against the following four PIs: amprenavir, JE-2147, RNI-272, and UIC-94003. Analyses of replication profiles of various mutant clones including competitive HIV-1 replication assays demonstrated that these mutations were indispensable for HIV-1 replication in the presence of PIs. When some of these mutations were reverted to wild type amino acids, such HIV-1 clones failed to replicate. However, virtually the same Gag cleavage pattern was seen, indicating that the mutations affected Gag protein functions but not their cleavage sensitivity to protease. These data strongly suggest that non-cleavage site amino acid substitutions in the Gag protein recover the reduced replicative fitness of HIV-1 caused by mutations in the viral protease and may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1.

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