SIV/HIV-1 hybrid virus expressing the reverse transcriptase gene of HIV-1 remains sensitive to HIV-1-specific reverse transcriptase inhibitors after passage in rhesus macaques.
We have previously described an animal model for the therapy of human immunodeficiency virus type 1 (HIV-1) infection with HIV-1-specific reverse transcriptase (RT) inhibitors based on a simian immunodeficiency virus (SIV), in which the RT gene of SIV was replaced by the RT gene of HIV-1. In vitro, replication of the hybrid virus, RT-SHIV, was delayed compared with parental SIV. RT-SHIV could induce AIDS-like symptoms and pathologic alterations in rhesus macaques. Characterization of re-isolates recovered from RT-SHIV-infected macaques one-half year after infection revealed that the re-isolates replicated with kinetics similar to those of SIV. Inefficient processing of the Gag-Pol precursor of RT-SHIV may be one reason for the retarded growth of RT-SHIV, because the protease cleavage site between the protease gene and the RT gene was frequently mutated in the RT-SHIV re-isolates. Adaptation of RT-SHIV to the growth in macaques did not result in a relevant loss of sensitivity to nonnucleoside RT inhibitors (NNRTIs). However, because a minor sub-population of the RT-SHIV re-isolates contained a mutation conferring low-level resistance to ddI and ddC, the RT-SHIV/macaque model may underestimate the efficacy of these drugs. Nevertheless, this report further supports the suitability, reliability, and usefulness of the RT-SHIV/macaque model to investigate the antiviral properties of most RT inhibitors in an in vivo setting.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
Uberla
K
K
D000818:Animals; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006824:Hybridization, Genetic; D008253:Macaca mulatta; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*
D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase