An in vivo model for HIV resistance development.
Treatment of human immunodeficiency virus (HIV-1) with drugs targeted to the reverse transcriptase (RT) rapidly selects for drug-resistant virus. It is essential to develop a suitable animal model that allows the study of the emergence and reversal of drug resistance. A monkey model was previously developed on the basis of a hybrid virus (RT-SHIV) of simian immunodeficiency virus (SIV) with its RT exchanged for HIV-1 RT. In the present study cynomolgus monkeys infected with RT-SHIV were treated with varying doses of the non-nucleoside RT inhibitor nevirapine. The drug was administered for 2-3 weeks, in agreement with clinical experience of resistance development during nevirapine monotherapy. This resulted in the selection of mutants with Y181C and K103N changes in RT, which correspond to the HIV-1 mutations in nevirapine-resistant HIV-1 patients. The mutants coexisted at varying levels with wild-type virus and fluctuations in the proportion of mutants could be closely monitored. Low-dose treatment was not more efficient in induction of mutations than a virus-inhibiting dose. Structured therapy interruptions could be performed. The monkey RT-SHIV infection offers an in vivo model to determine effects of therapies on resistance development.
Zuber
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B
Virology Department, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden. bartek.zuber@smi.ki.se
Böttiger
D
D
Benthin
R
R
ten Haaft
P
P
Heeney
J
J
Wahren
B
B
Oberg
B
B
D000818:Animals; D002678:Chimera; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D008252:Macaca fascicularis; D019829:Nevirapine / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics
D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase