Rabbit Anti-Human PRKDC (Phospho-Thr2647) polyclonal antibody

The goal of the current studies was to determine the risk of transmission of mouse parvovirus (MPV) by caging and husbandry practices. To determine whether MPV can be transmitted during cage changes in a biologic safety cabinet without the use of disinfectants, 14 cages of Swiss Webster mice were inoculated with MPV. Cages containing infected mice were interspersed among 14 cages housing naive Swiss Webster mice. At 1, 2, and 4 wk after inoculation of the mice, cages were changed across each row. All naive mice housed adjacent to infected mice remained seronegative. To determine the risk of environmental contamination, nesting pads that were used to sample the room floor during husbandry procedures at 1, 2, 4, and 6 wk after inoculation of, the mice were placed in cages with naive mice. None of the mice exposed to the pads became MPV seropositive. To determine whether components from cages that had housed MPV-infected mice could transmit MPV, Swiss Webster mice were exposed to soiled bedding or used cages, drinking valves, food, cage bottoms, wire bars and filter tops, nesting material, or shelters. With the exception of drinking valves, all mice exposed to other components became MPV seropositive. Fourteen cages that had housed MPV-infected mice were washed but not autoclaved; mice housed in the washed cages did not become MPV seropositive. In conclusion, all cage components can serve as fomites, with the drinking valve being the least risky. Cage washing alone was sufficient to remove or inactivate MPV.

Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PIs). Plasma drug concentrations are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited since the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism. Thus, we created a mouse strain with the human pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 genes on a NOD. Cg-Prkdc(scid) II2rg(tm1Sug)/JicTac background (hCYP3A-NOG) and used them to evaluate the impact of human CYP3A metabolism on ARV pharmacokinetics. In proof-of-concept studies we used nanoformulated atazanavir (nanoATV) with or without RTV. NOG and hCYP3A-NOG mice were treated weekly with 50 mg/kg nanoATV alone or boosted with nanoformulated ritonavir (nanoATV/r). Plasma was collected weekly and liver was collected at 28 days post-treatment. Plasma and liver atazanavir (ATV) concentrations in nanoATV/r-treated hCYP3A-NOG mice were 2- to 4-fold higher than in replicate NOG mice. RTV enhanced plasma and liver ATV concentrations 3-fold in hCYP3A-NOG mice and 1.7-fold in NOG mice. The results indicate that human CYP3A-mediated drug metabolism is reduced compared with mouse and that RTV differentially affects human gene activity. These differences can affect responses to PIs in humanized mouse models of HIV-1 infection. Importantly, hCYP3A-NOG mice reconstituted with human immune cells can be used for bench-to-bedside translation.