Abstract
BackgroundIn vivo studies of HIV-1 pathogenesis and testing of antiviral strategies have been hampered by the lack of an immunocompetent small animal model that is highly susceptible to HIV-1 infection. Although transgenic rats that express the HIV-1 receptor complex hCD4 and hCCR5 are susceptible to infection, HIV-1 replicates very poorly in these animals. To demonstrate the molecular basis for developing a better rat model for HIV-1 infection, we evaluated the effect of human CyclinT1 (hCycT1) and CRM1 (hCRM1) on Gag p24 production in rat T cells and macrophages using both established cell lines and primary cells prepared from hCycT1/hCRM1 transgenic rats.ResultsExpression of hCycT1 augmented Gag production 20–50 fold in rat T cells, but had little effect in macrophages. Expression of hCRM1 enhanced Gag production 10–15 fold in macrophages, but only marginally in T cells. Expression of both factors synergistically enhanced p24 production to levels approximately 10–40% of those detected in human cells. R5 viruses produced in rat T cells and macrophages were fully infectious.ConclusionThe expression of both hCycT1 and hCRM1 appears to be fundamental to developing a rat model that supports robust propagation of HIV-1.
Highlights
In vivo studies of HIV-1 pathogenesis and testing of antiviral strategies have been hampered by the lack of an immunocompetent small animal model that is highly susceptible to HIV1 infection
We investigated the effect of human CyclinT1 and CRM1 expressed in rat T cells and macrophages, including primary cells, in order to identify a molecular basis for improving a rat model for HIV-1 infection
Synergistic Effects of human CyclinT1 (hCycT1) and hCRM1 in Rat T cell lines Since controversial results regarding the activity of Tat in rat cells have been reported, we compared the effect of hCycT1 versus rCycT1expression in rat T cells
Summary
In vivo studies of HIV-1 pathogenesis and testing of antiviral strategies have been hampered by the lack of an immunocompetent small animal model that is highly susceptible to HIV1 infection. Current animal models of HIV infection, including non-human primates [1,2,3,4] and severe combined immunodeficiency (SCID) mice transplanted with fetal human cells [5,6], have made significant contributions to our understanding of lentiviral pathogenesis and to the development of vaccines and therapeutic agents. These models have shortcomings, such as their limited availability and high cost, their permissivity restricted to related retroviruses of nonhuman primates, as well as the absence or insufficient induction of an immune response against HIV-1.
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