Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy

Zandrea Ambrose, Sarah Palmer, Valerie F. Boltz, Mary Kearney, Kay Larsen, Patricia Polacino, Leon Flanary, Kelli Oswald, Michael Piatak, Jeremy Smedley, Wei Shao, Norbert Bischofberger, Frank Maldarelli, Jason T. Kimata, John W. Mellors, Shiu Lok Hu, John M. Coffin, Jeffrey D. Lifson, Vineet N. KewalRamani

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does not clear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

Original languageEnglish (US)
Pages (from-to)12145-12155
Number of pages11
JournalJournal of Virology
Volume81
Issue number22
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Viremia
viremia
drug resistance
Macaca
Human immunodeficiency virus 1
Drug Resistance
HIV-1
RNA-directed DNA polymerase
Reverse Transcriptase Inhibitors
therapeutics
Macaca nemestrina
Therapeutics
Mothers
Musculoskeletal Manipulations
Simian Immunodeficiency Virus
Simian immunodeficiency virus
animals
Infection
nucleosides
Nucleosides

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Ambrose, Z., Palmer, S., Boltz, V. F., Kearney, M., Larsen, K., Polacino, P., ... KewalRamani, V. N. (2007). Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy. Journal of Virology, 81(22), 12145-12155. https://doi.org/10.1128/JVI.01301-07

Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy. / Ambrose, Zandrea; Palmer, Sarah; Boltz, Valerie F.; Kearney, Mary; Larsen, Kay; Polacino, Patricia; Flanary, Leon; Oswald, Kelli; Piatak, Michael; Smedley, Jeremy; Shao, Wei; Bischofberger, Norbert; Maldarelli, Frank; Kimata, Jason T.; Mellors, John W.; Hu, Shiu Lok; Coffin, John M.; Lifson, Jeffrey D.; KewalRamani, Vineet N.

In: Journal of Virology, Vol. 81, No. 22, 01.11.2007, p. 12145-12155.

Research output: Contribution to journalArticle

Ambrose, Z, Palmer, S, Boltz, VF, Kearney, M, Larsen, K, Polacino, P, Flanary, L, Oswald, K, Piatak, M, Smedley, J, Shao, W, Bischofberger, N, Maldarelli, F, Kimata, JT, Mellors, JW, Hu, SL, Coffin, JM, Lifson, JD & KewalRamani, VN 2007, 'Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy', Journal of Virology, vol. 81, no. 22, pp. 12145-12155. https://doi.org/10.1128/JVI.01301-07
Ambrose, Zandrea ; Palmer, Sarah ; Boltz, Valerie F. ; Kearney, Mary ; Larsen, Kay ; Polacino, Patricia ; Flanary, Leon ; Oswald, Kelli ; Piatak, Michael ; Smedley, Jeremy ; Shao, Wei ; Bischofberger, Norbert ; Maldarelli, Frank ; Kimata, Jason T. ; Mellors, John W. ; Hu, Shiu Lok ; Coffin, John M. ; Lifson, Jeffrey D. ; KewalRamani, Vineet N. / Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy. In: Journal of Virology. 2007 ; Vol. 81, No. 22. pp. 12145-12155.
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