Enhanced antiretroviral therapy in rhesus macaques improves RT-SHIV viral decay kinetics

Thomas W. North, Andradi Villalobos, Selwyn J. Hurwitz, Jesse D. Deere, Joanne Higgins, Payel Chatterjee, Sijia Tao, Robert C. Kauffman, Paul A Luciw, James J. Kohler, Raymond F. Schinazi

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3927-3933
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number7
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

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    North, T. W., Villalobos, A., Hurwitz, S. J., Deere, J. D., Higgins, J., Chatterjee, P., Tao, S., Kauffman, R. C., Luciw, P. A., Kohler, J. J., & Schinazi, R. F. (2014). Enhanced antiretroviral therapy in rhesus macaques improves RT-SHIV viral decay kinetics. Antimicrobial Agents and Chemotherapy, 58(7), 3927-3933. https://doi.org/10.1128/AAC.02522-14