Human Immunodeficiency Virus Type 1 Restriction by Human–Rhesus Chimeric Tripartite Motif 5α (TRIM 5α) in CD34+ Cell-Derived Macrophages In Vitro and in T Cells In Vivo in Severe Combined Immunodeficient (SCID-hu) Mice Transplanted with Human Fetal Tissue

摘要

Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. Thenretroviral restriction factor TRIM5u0002 (tripartite motif 5u0002 protein) has been shown to potently restrict humannimmunodeficiency virus (HIV)-1 infection in otherwise susceptible cell lines and CD34u0002 cell-derived macrophages.nA 13-amino acid patch in the C-terminal B30.2 (SPRY) domain of rhesus macaque TRIM5u0002 has beennshown to be involved in HIV-1 capsid recognition and is critical for viral inhibition. A chimeric human–rhesusnTRIM5u0002 (TRIM5u0002-HRH) was generated by replacing an 11-amino acid patch in the human isoform withnthe rhesus 13-amino acid patch. Here we show that lentiviral vector expression of this human–rhesus chimeranin HIV-1-permissive MAGI-CXCR4 cells conferred resistance as well as a selective survival advantage onnHIV-1 challenge. To apply these findings in a stem cell gene therapy setting, TRIM5u0002-HRH was expressed innCD34u0002 cell-derived macrophages in vitro and in SCID-hu mouse-derived thymocytes in vivo. On viral challenge,ntransgenic macrophages and thymocytes were highly resistant to HIV-1 compared with control cells.nNormal development of TRIM5u0002-HRH-expressing macrophages and in vivo-derived T cells was also observednby phenotypic flow cytometric analysis. These results demonstrate the efficacy of TRIM5u0002-HRH in a stemncell setting and its further advancement for use in gene therapy applications.