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Antimicrobial Agents and Chemotherapy, October 1999, p. 2479-2483, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

In Vitro Induction of Human Immunodeficiency Virus Type 1 Variants Resistant to Phosphoralaninate Prodrugs of Z-Methylenecyclopropane Nucleoside Analogues

Kazuhisa Yoshimura,1 Ron Feldman,1 Eiichi Kodama,1 Mark F. Kavlick,1 Yao-Ling Qiu,2 Jiri Zemlicka,2 and Hiroaki Mitsuya1,3,*

Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208921; Department of Chemistry, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 482012; HIV Clinical Interface Laboratory, Developmental Therapeutics Program, SAIC/NCI-FCRDC, Frederick, Maryland 21702; and Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860, Japan3

Received 5 April 1999/Returned for modification 1 July 1999/Accepted 6 August 1999

Two methylenecyclopropane nucleoside analogues with a phenylphosphoralaninate moiety, QYL-685 and QYL-609, exert potent and specific activities against human immunodeficiency virus type 1 strain LAI (HIV-1LAI) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1LAI to increasing concentrations of QYL-685. After 16 passages, the virus (HIV-1P16) was less sensitive to QYL-685 (104-fold), QYL-609 (>41-fold), and (-)-beta -2',3'-dideoxy-3'-thiacytidine (3TC) (>1,100-fold) than was HIV-1LAI and contained an M184I mutation. Two infectious clones, HIV-1M184I and HIV-1M184V, were resistant to QYL-685, QYL-609, and 3TC, confirming that the M184I mutation was responsible for the observed resistance. Viral-fitness analyses (competitive HIV-1 replication assays) revealed that in the absence of drugs, M184I and M184V conferred a replication disadvantage on the virus compared to the replication efficiency of the wild-type infectious clone (HIV-1wt). However, in the presence of QYL-685 (4 µM), HIV-1M184I and HIV-1M184V showed greater fitness than HIV-1wt. These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.

* Corresponding author. Mailing address: Experimental Retrovirology Section, Medicine Branch, National Cancer Institute, Bldg. 10, Room 5A11, 9000 Rockville Pk., Bethesda, MD 20892. Phone: (301) 496-9238. Fax: (301) 402-0709. E-mail: hmitsuya{at}helix.nih.gov.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2479-2483, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.




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