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

Joseph S Anderson, Ramesh Akkina

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. The retroviral restriction factor TRIM5α (tripartite motif 5α protein) has been shown to potently restrict human immunodeficiency virus (HIV)-1 infection in otherwise susceptible cell lines and CD34+ cell-derived macrophages. A 13-amino acid patch in the C-terminal B30.2 (SPRY) domain of rhesus macaque TRIM5α has been shown to be involved in HIV-1 capsid recognition and is critical for viral inhibition. A chimeric human-rhesus TRIM5α (TRIM5α-HRH) was generated by replacing an 11-amino acid patch in the human isoform with the rhesus 13-amino acid patch. Here we show that lentiviral vector expression of this human-rhesus chimera in HIV-1-permissive MAGI-CXCR4 cells conferred resistance as well as a selective survival advantage on HIV-1 challenge. To apply these findings in a stem cell gene therapy setting, TRIM5α-HRH was expressed in CD34+ cell-derived macrophages in vitro and in SCID-hu mouse-derived thymocytes in vivo. On viral challenge, transgenic macrophages and thymocytes were highly resistant to HIV-1 compared with control cells. Normal development of TRIM5α-HRH-expressing macrophages and in vivo-derived T cells was also observed by phenotypic flow cytometric analysis. These results demonstrate the efficacy of TRIM5α-HRH in a stem cell setting and its further advancement for use in gene therapy applications.

Original languageEnglish (US)
Pages (from-to)217-228
Number of pages12
JournalHuman Gene Therapy
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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SCID Mice
HIV-1
Fetus
Macrophages
T-Lymphocytes
Virus Diseases
Thymocytes
Amino Acids
Genetic Therapy
Stem Cells
Amino Acid Motifs
Capsid
Cell- and Tissue-Based Therapy
Macaca mulatta
Antiviral Agents
Tripartite Motif Proteins
In Vitro Techniques
Protein Isoforms
Cell Line
Survival

ASJC Scopus subject areas

  • Genetics

Cite this

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title = "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",
abstract = "Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. The retroviral restriction factor TRIM5α (tripartite motif 5α protein) has been shown to potently restrict human immunodeficiency virus (HIV)-1 infection in otherwise susceptible cell lines and CD34+ cell-derived macrophages. A 13-amino acid patch in the C-terminal B30.2 (SPRY) domain of rhesus macaque TRIM5α has been shown to be involved in HIV-1 capsid recognition and is critical for viral inhibition. A chimeric human-rhesus TRIM5α (TRIM5α-HRH) was generated by replacing an 11-amino acid patch in the human isoform with the rhesus 13-amino acid patch. Here we show that lentiviral vector expression of this human-rhesus chimera in HIV-1-permissive MAGI-CXCR4 cells conferred resistance as well as a selective survival advantage on HIV-1 challenge. To apply these findings in a stem cell gene therapy setting, TRIM5α-HRH was expressed in CD34+ cell-derived macrophages in vitro and in SCID-hu mouse-derived thymocytes in vivo. On viral challenge, transgenic macrophages and thymocytes were highly resistant to HIV-1 compared with control cells. Normal development of TRIM5α-HRH-expressing macrophages and in vivo-derived T cells was also observed by phenotypic flow cytometric analysis. These results demonstrate the efficacy of TRIM5α-HRH in a stem cell setting and its further advancement for use in gene therapy applications.",
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T1 - 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

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N2 - Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. The retroviral restriction factor TRIM5α (tripartite motif 5α protein) has been shown to potently restrict human immunodeficiency virus (HIV)-1 infection in otherwise susceptible cell lines and CD34+ cell-derived macrophages. A 13-amino acid patch in the C-terminal B30.2 (SPRY) domain of rhesus macaque TRIM5α has been shown to be involved in HIV-1 capsid recognition and is critical for viral inhibition. A chimeric human-rhesus TRIM5α (TRIM5α-HRH) was generated by replacing an 11-amino acid patch in the human isoform with the rhesus 13-amino acid patch. Here we show that lentiviral vector expression of this human-rhesus chimera in HIV-1-permissive MAGI-CXCR4 cells conferred resistance as well as a selective survival advantage on HIV-1 challenge. To apply these findings in a stem cell gene therapy setting, TRIM5α-HRH was expressed in CD34+ cell-derived macrophages in vitro and in SCID-hu mouse-derived thymocytes in vivo. On viral challenge, transgenic macrophages and thymocytes were highly resistant to HIV-1 compared with control cells. Normal development of TRIM5α-HRH-expressing macrophages and in vivo-derived T cells was also observed by phenotypic flow cytometric analysis. These results demonstrate the efficacy of TRIM5α-HRH in a stem cell setting and its further advancement for use in gene therapy applications.

AB - Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. The retroviral restriction factor TRIM5α (tripartite motif 5α protein) has been shown to potently restrict human immunodeficiency virus (HIV)-1 infection in otherwise susceptible cell lines and CD34+ cell-derived macrophages. A 13-amino acid patch in the C-terminal B30.2 (SPRY) domain of rhesus macaque TRIM5α has been shown to be involved in HIV-1 capsid recognition and is critical for viral inhibition. A chimeric human-rhesus TRIM5α (TRIM5α-HRH) was generated by replacing an 11-amino acid patch in the human isoform with the rhesus 13-amino acid patch. Here we show that lentiviral vector expression of this human-rhesus chimera in HIV-1-permissive MAGI-CXCR4 cells conferred resistance as well as a selective survival advantage on HIV-1 challenge. To apply these findings in a stem cell gene therapy setting, TRIM5α-HRH was expressed in CD34+ cell-derived macrophages in vitro and in SCID-hu mouse-derived thymocytes in vivo. On viral challenge, transgenic macrophages and thymocytes were highly resistant to HIV-1 compared with control cells. Normal development of TRIM5α-HRH-expressing macrophages and in vivo-derived T cells was also observed by phenotypic flow cytometric analysis. These results demonstrate the efficacy of TRIM5α-HRH in a stem cell setting and its further advancement for use in gene therapy applications.

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