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.