Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1.
The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 +/- 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.
Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
Michael J
MJ
Hofman
Joanne
J
Higgins
Timothy B
TB
Matthews
Niels C
NC
Pedersen
Chalet
C
Tan
Raymond F
RF
Schinazi
Thomas W
TW
North
D000480:Alkynes; D000818:Animals; D048588:Benzoxazines; D016516:CD4-CD8 Ratio; D002678:Chimera / Q000235:genetics; D003521:Cyclopropanes; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D005434:Flow Cytometry; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008253:Macaca mulatta; D009154:Mutation / Q000235:genetics; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000096:biosynthesis; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D017931:DNA Primers; D004279:DNA, Viral; D010078:Oxazines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz