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J. Biol. Chem., Vol. 277, Issue 8, 5952-5961, February 22, 2002
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From the 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.
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*
§,
,
,
¶,
,
,
,
,
, and
¶§§
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

Howard Hughes Medical Institute and
Department of Chemistry and Biochemistry, University of Maryland,
Baltimore, Maryland 21250
*
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.
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