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Journal of Virology, July 1999, p. 5356-5363, Vol. 73, No. 7
0022-538X/99/$04.00+0

Comparative Fitness of Multi-Dideoxynucleoside-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) in an In Vitro Competitive HIV-1 Replication Assay

Pope Kosalaraksa,1 Mark F. Kavlick,1 Victor Maroun,1 Richard Le,1 and Hiroaki Mitsuya1,2,*

Experimental Retrovirology Section, Department of Developmental Therapeutics, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,1 and Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860, Japan2

Received 7 October 1998/Accepted 24 March 1999

We examined whether human immunodeficiency virus type 1 (HIV-1) fitness was altered upon the acquisition of a set or subset of five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the pol gene, which confers resistance to multiple dideoxynucleosides (MDR), as well as the zidovudine resistance-associated mutation T215Y, using a competitive HIV-1 replication assay in a setting of an HXB2D genetic background. Target H9 cells were exposed to a 50:50 mixture of paired infectious molecular clones, and HIV-1 in the culture supernatant was transmitted to new cultures every 7 to 10 days. The polymerase-encoding region of the virus was sequenced at various time points, and the relative proportion of the two viral populations was determined. In the absence of drugs, the comparative order for replicative fitness was HIV-162/75/77/116/151 > HIV-177/116/151 > HIV-1151 > wild-type HIV-1 (HIV-1wt) > HIV-175/77/116/151 > HIV-1151/215 > HIV-1215. In the presence of zidovudine or didanosine, the order was HIV-162/75/77/116/151 > HIV-177/116/151 > HIV-175/77/116/151 > HIV-1151 > HIV-1215. HIV-1215S(TCC), a putative intermediate infectious clone for HIV-1215, replicated comparably to HIV-1wt, while two putative intermediates for HIV-1151 [HIV-1151L(CTG) and HIV-1151K(AAG)] replicated much less efficiently than HIV-1wt and HIV-1151, suggesting that for HIV-1151 to develop, two base substitutions are likely to occur concurrently or within a short interval. These data may illustrate the molecular basis by which HIV-1151 emerges much less frequently than HIV-1215. The present data also demonstrate that several MDR HIV-1 variants are more fit than HIV-1wt in the absence of drugs and that resistance-associated mutations and drug pressure are critical variates for HIV-1 fitness.

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

Journal of Virology, July 1999, p. 5356-5363, Vol. 73, No. 7
0022-538X/99/$04.00+0


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