Transgenic expression of the human LEDGF/p75 gene relieves the species barrier against HIV-1 infection in mouse cells

Takuya Tada,Yoichiro Iwakura,Kenzo Tokunaga,Yang Liu,Motohiko Kadoki

doi:10.3389/fmicb.2013.00377

Abstract

Attempts to create mouse models for AIDS have been hampered by species barriers in HIV-1 infection. We previously showed that the nuclear accumulation of HIV-1 preintegration complex (PIC) was suppressed in mouse cells. Lens epithelium-derived growth factor (LEDGF/p75) is a host factor identified as a binding partner of integrase (IN), and has been suggested to be involved in promoting viral integration by tethering PIC to the chromatin, which are observed as nuclear accumulation of IN by LEDGF/p75. Therefore, we here hypothesized that this host factor might act as one of the species-specific barriers in mouse cells. We generated transgenic (Tg) mice that constitutively express human (h) LEDGF/p75. The GFP-fused IN was efficiently accumulated into the nucleus of hLEDGF/p75 expressing Tg mouse embryonic fibroblast (MEF) cells in contrast to the control MEF cells. Importantly, hLEDGF/p75 Tg MEF cells were significantly more susceptible to HIV-1 infection. These results suggest that LEDGF/p75 is one of the host factors that constitute species barrier against HIV-1 in mouse cells.

Highlights

The number of patients with HIV/AIDS has been increasing throughout the world
FUNCTIONAL DIFFERENCE BETWEEN HUMAN AND MURINE Lens epithelium-derived growth factor (LEDGF)/p75 PROTEINS We previously showed that the nuclear accumulation of preintegration complex (PIC) was blocked in mouse cells (Tsurutani et al, 2007), suggesting that mLEDGF/p75 might be defective at this step
We examined the efficiency of HIV-1 infection by using mouse embryonic fibroblast (MEF) cells transiently expressing hLEDGF/p75 or mLEDGF/p75

Summary

Introduction

The number of patients with HIV/AIDS has been increasing throughout the world. In order to study AIDS pathogenesis and to evaluate antiviral drugs and vaccines, animal models for HIV-1 infection need to be established. Tg mice carrying the pol gene-deleted HIV-1 proviral genome (HIVTg), which we previously generated, were able to express all viral mRNA species, including unspliced, singly spliced, and multiply spliced mRNAs, and produce high levels of gag p24 antigen, after treatment with bacterial lipopolysaccharides (LPS) (Iwakura et al, 1992). Taken together, these results indicate that once the viral genome is efficiently integrated into the host chromosome, viral genes are expressed normally, and that unknown species barriers in mice are still present in the early phase of HIV-1 infection

Methods

Results

Conclusion