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Journal of Virology, July 1999, p. 5356-5363, Vol. 73, No. 7
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.
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
*
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.
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