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Journal of Virology, July 2006, p. 7020-7027, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.02747-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Fitness Comparison of Thymidine Analog Resistance Pathways in Human Immunodeficiency Virus Type 1

Zixin Hu, Françoise Giguel, Hiroyu Hatano, Patrick Reid, Jing Lu, and Daniel R. Kuritzkes*

Section of Retroviral Therapeutics, Brigham and Women's Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts

Received 31 December 2005/ Accepted 11 May 2006

Resistance to zidovudine (ZDV) results from thymidine analog resistance mutations (TAMs) at human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) codons 41, 67, 70, 210, 215, and 219. Two mutations are possible at codon 215: Y or F. Whereas T215Y occurs alone or with M41L and L210W (TAM-1 pattern), T215F rarely occurs with these mutations or by itself; it is found instead with D67N, K70R, and K219Q (TAM-2 pattern). The L210W mutation most often occurs with M41L and T215Y and rarely occurs with the T215F or TAM-2 mutation. To explain these associations, TAMs were introduced into HIV-1Hxb2 by site-directed mutagenesis and expressed in recombinant viruses. Viral replication kinetics, relative fitness, and infectivity were tested in the absence or presence of ZDV. Viruses carrying the 215Y mutation showed faster replication kinetics and greater relative fitness than did T215F mutants in the absence or presence of ZDV. In addition, T215Y mutants showed greater infectivity than did wild-type HIV-1 over a range of ZDV concentrations, but T215F mutants had only a modest advantage over the wild-type virus. Whereas introduction of L210W improved the relative fitness of an M41L/T215Y mutant in the presence of ZDV, introduction of this mutation into a D67N/K70R/K219Q background resulted in decreased relative fitness in the presence or absence of drug. By contrast, introduction of T215F into the D67N/K70R/K219Q background increased viral fitness in the presence of ZDV. These results help explain why T215Y but not T215F usually emerges as the first major TAM, as well as the clustering of L210W with TAM-1 mutations and T215F with TAM-2 mutations.

* Corresponding author. Mailing address: Brigham and Women's Hospital, 65 Landsdowne Street, Room 449, Cambridge, MA 02139. Phone: (617) 768-8371. Fax: (617) 768-8738. E-mail: dkuritzkes{at}partners.org.

Journal of Virology, July 2006, p. 7020-7027, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.02747-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Armstrong, K. L., Lee, T.-H., Essex, M. (2009). Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1. J. Virol. 83: 4051-4059 [Abstract] [Full Text]  
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