Enhanced antiretroviral therapy in rhesus macaques improves RT-SHIV viral decay kinetics.
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 >10(4) 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.
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA University of California Davis, Davis, California, USA.
Thomas W
TW
North
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA.
Andradi
A
Villalobos
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Selwyn J
SJ
Hurwitz
University of California Davis, Davis, California, USA.
Jesse D
JD
Deere
University of California Davis, Davis, California, USA.
Joanne
J
Higgins
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Payel
P
Chatterjee
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Sijia
S
Tao
University of California Davis, Davis, California, USA.
Robert C
RC
Kauffman
University of California Davis, Davis, California, USA.
Paul A
PA
Luciw
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
James J
JJ
Kohler
Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA rschina@emory.edu.
Raymond F
RF
Schinazi
D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D004338:Drug Combinations; D007700:Kinetics; D008253:Macaca mulatta; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology*; D015302:Simian Immunodeficiency Virus; D019562:Viral Load
D019380:Anti-HIV Agents; D004338:Drug Combinations; D012367:RNA, Viral