Construction of a novel SHIV having an HIV-1-derived protease gene and its infection to rhesus macaques: a useful tool for in vivo efficacy tests of protease inhibitors.
We generated a novel SHIV (termed SHIV-pr) that possesses the HIV-1-derived protease (PR) gene in the corresponding position in the SIVmac genome. SHIV-pr is replication-competent in human and monkey CD4(+) T lymphoid cell lines as well as rhesus macaque PBMCs. The viral growth of SHIV-pr was completely blocked in the presence of a peptide-analog PR inhibitor at the tissue culture level. When SHIV-pr was intravenously inoculated into two rhesus macaques, it resulted in a weak but long-lasting persistent infection in one monkey, whereas the infection of another was only temporary. To enhance the viral growth competence by adaptation, we then passaged the virus in vivo from a monkey up to the fourth generation. The initial peak values of plasma viral loads as well as the setpoint values increased generation by generation and reached those of a parental virus SIVmac. When a medication using the content of Kaletra capsule (a mixture of two PR inhibitors, lopinavir and ritonavir) was orally given to three SHIV-pr-infected monkeys for 4 weeks, plasma viral loads dropped to near or below the detection limit and quickly rebounded after the cessation of medication. The results suggest that SHIV-pr can be used to evaluate PR inhibitors using monkeys.
Ishimatsu
Misa
M
Laboratory for Viral Replication, Center for Emerging Virus Research, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaracho, Kyoto 606-8507, Japan.
Suzuki
Hajime
H
Akiyama
Hisashi
H
Miura
Tomoyuki
T
Hayami
Masanori
M
Ido
Eiji
E
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002678:Chimera / Q000821:virology*; D015683:Gene Products, gag / Q000378:metabolism; D016333:HIV Protease / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear; D061466:Lopinavir; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development; D014162:Transfection; D019562:Viral Load; D014779:Virus Replication
D015683:Gene Products, gag; D009842:Oligopeptides; D011480:Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease; C077822:kynostatin 272