TRIM5alpharh expression restricts HIV-1 infection in lentiviral vector-transduced CD34+-cell-derived macrophages.
Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutic and prophylactic approaches. The retroviral and lentiviral restriction factors Ref1 and Lv1 are variants of the tripartite motif protein TRIM5alpha, a component of cytoplasmic bodies. TRIM5alpha severely restricts productive retroviral infections at the postentry and preintegration steps by destabilizing the incoming viral capsid via ubiquitination. Using this approach, resistance to HIV-1 infection could be conferred by TRIM5alpha(rh) expression in otherwise susceptible cells. Here we show that stable expression of simian TRIM5alpha(rh) via a lentiviral vector in a permissive cell culture line, Magi-CXCR4, conferred resistance to HIV-1. To translate these findings into a stem cell gene therapy setting, the TRIM5alpha(rh) transgene was stably introduced into CD34(+) hematopoietic progenitor cells to derive transgenic macrophages. Upon viral challenge, TRIM5alpha(rh)-expressing macrophages were highly resistant to HIV-1 infection compared to control cells. Human macrophages expressing TRIM5alpha(rh) were also found to be phenotypically and functionally normal, expressing the characteristic surface markers CD14, CD4, CCR5, CXCR4, MHC II, and B7.1. These results demonstrate that the species-specific restriction factor TRIM5alpha(rh) is effective in conferring HIV-1 resistance in a stem cell setting, thus paving the way for its application in AIDS gene therapy.
Anderson
Joseph
J
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, 80523, USA.
Akkina
Ramesh
R
D018952:Antigens, CD34; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006412:Hematopoietic Stem Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014161:Transduction, Genetic; D019076:Transgenes; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D018952:Antigens, CD34; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases