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Journal of Virology, November 2004, p. 12030-12040, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.12030-12040.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors

Sadahiro Tamiya,1 Sek Mardy,1 Mark F. Kavlick,1 Kazuhisa Yoshimura,2 and Hiroaki Mistuya1,3*

Experimental Retovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland,1 Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research,2 Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan3

Received 10 February 2004/ Accepted 24 June 2004

A variety of amino acid substitutions in the protease and Gag proteins have been reported to contribute to the development of human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors. In the present study, full-length molecular infectious HIV-1 clones were generated by using HIV-1 variants isolated from heavily drug-experienced and therapy-failed AIDS patients. Of six full-length infectious clones generated, four were found to have unique insertions (TGNS, SQVN, AQQA, SRPE, APP, and/or PTAPPA) near the p17/p24 and p1/p6 Gag cleavage sites, in addition to the known resistance-related multiple amino acid substitutions within the protease. The addition of such Gag inserts mostly compromised the replication of wild-type HIV-1, whereas the primary multidrug-resistant HIV infectious clones containing inserts replicated significantly better than those modified to lack the inserts. Western blot analyses revealed that the processing of Gag proteins by wild-type protease was impaired by the presence of the inserts, whereas that by mutant protease was substantially improved. The present study represents the first report clearly demonstrating that the inserts seen in the proximity of the Gag cleavage sites in highly multi-PI resistant HIV-1 variants restore the otherwise compromised enzymatic activity of mutant protease, enabling the multi-PI-resistant HIV-1 variants to remain replication competent.

* Corresponding author. Mailing address: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer, Institute/NIH, Bldg. 10, Rm. 5A11, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 402-3631. Fax: (301) 402-0709. E-mail: hmitsuya{at}helix.nih.gov.

Journal of Virology, November 2004, p. 12030-12040, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.12030-12040.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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