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Originally published In Press as doi:10.1074/jbc.M108005200 on December 10, 2001

J. Biol. Chem., Vol. 277, Issue 8, 5952-5961, February 22, 2002
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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*

Hiroyuki GatanagaDagger §, Yasuhiro SuzukiDagger , Hsinyi TsangDagger , Kazuhisa YoshimuraDagger , Mark F. KavlickDagger , Kunio Nagashima||, Robert J. Gorelick**, Sek MardyDagger , Chun TangDagger Dagger , Michael F. SummersDagger Dagger , and Hiroaki MitsuyaDagger §§

From the Dagger  Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, the  Department of Internal Medicine II, Kumamoto University School of Medicine, Honjo 1-1-1 Kumamoto 860, Japan, the || Image Analysis Laboratory and ** AIDS Vaccine Program, Science Applications International Corporation, NCI, Frederick, Maryland 21702, and the Dagger Dagger  Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Maryland, Baltimore, Maryland 21250

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, KNI-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.

* This work was supported in part by a Grant from Research for Future Program JSPS-RFTF 97L00705 of the Japan Society for the Promotion of Science, a grant-in-aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu-Kagakusho), a grant for Promotion of AIDS Research from the Ministry of Health, Welfare and Labor of Japan (Kosei-Rohdosho), and by Science Applications International Corp. NCI-Frederick Grants N01-CO 56000 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported in part by the grant from the Japanese Foundation for AIDS Prevention.

§§ To whom correspondence should be addressed: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, Bldg. 10, Rm. 5A11, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-9238; Fax: 301-402-0709; E-mail: hmitsuya@helix.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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