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Author Notes:

E-mail Address : rschina@emory.edu

We thank Daria Hazuda for her contributions to the studies and her editorial suggestions. Special thanks are due to the UC Davis Lucy Whittier Molecular and Diagnostic Core Facility for performing some of the viral-load assays.

We also thank K. Van Rompay, L. Hirst, T. Dearman, A. Spinner, R. Tarara, D. Canfield, and others on the veterinary staff, Colony Services and Clinical Laboratory of the California National Primate Research Center, for expert technical assistance.

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Research Funding:

The studies were supported by NIH 8R01OD011094 (T.W.N. and R.F.S.) and 1RO1MH100999 (R.F.S.), by the Department of Veterans Affairs (R.F.S.), and in part by the Emory Center for AIDS Research (P30 AI050409).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Microbiology
  • Pharmacology & Pharmacy
  • MICROBIOLOGY
  • PHARMACOLOGY & PHARMACY
  • SIMIAN IMMUNODEFICIENCY VIRUS
  • REVERSE-TRANSCRIPTASE INHIBITORS
  • NONHUMAN PRIMATE MODEL
  • COMBINATION THERAPY
  • ANIMAL-MODEL
  • HIV
  • TYPE-1
  • AIDS
  • PHARMACOKINETICS
  • ERADICATION

Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics

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Journal Title:

Antimicrobial Agents and Chemotherapy

Volume:

Volume 58, Number 7

Publisher:

, Pages 3927-3933

Type of Work:

Article | Final Publisher PDF

Abstract:

Using an established nonhuman primate model, rhesus macaques were infected intravenously with a chimeric simian immunodeficiency virus (SIV) consisting of SIVmac239 with the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase from clone HXBc2 (RT-SHIV). The impacts of two enhanced (four- and five-drug) highly active antiretroviral therapies (HAART) on early viral decay and rebound were determined. The four-drug combination consisted of an integrase inhibitor, L-870-812 (L-812), together with a three-drug regimen comprising emtricitabine [(-)-FTC], tenofovir (TFV), and efavirenz (EFV). The five-drug combination consisted of one analog for each of the four DNA precursors {using TFV, (-)-FTC, (-)-β-D-(2R,4R)-1,3-dioxolane-2,6- diaminopurine (amdoxovir [DAPD]), and zidovudine (AZT)}, together with EFV. A cohort treated with a three-drug combination of (-)-FTC, TFV, and EFV served as treated controls. Daily administration of a three-, four-, or five-drug combination of antiretroviral agents was initiated at week 6 or 8 after inoculation and continued up to week 50, followed by a rebound period. Plasma samples were collected routinely, and drug levels were monitored using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Viral loads were monitored with a standard TaqMan quantitative reverse transcriptase PCR (qRT-PCR) assay. Comprehensive analyses of replication dynamics were performed. RT-SHIV infection in rhesus macaques produced typical viral infection kinetics, with untreated controls establishing persistent viral loads of >104 copies of RNA/ml. RT-SHIV loads at the start of treatment (V0) were similar in all treated cohorts (P > 0.5). All antiretroviral drug levels were measureable in plasma. The four-drug and five-drug combination regimens (enhanced HAART) improved suppression of the viral load (within 1 week; P < 0.01) and had overall greater potency (P < 0.02) than the three-drug regimen (HAART). Moreover, rebound viremia occurred rapidly following cessation of any treatment. The enhanced HAART (four- or five-drug combination) showed significant improvement in viral suppression compared to the three-drug combination, but no combination was sufficient to eliminate viral reservoirs. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Copyright information:

© 2014, American Society for Microbiology.

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