Transduction of CD34+ hematopoietic progenitor cells with an antitat gene protects T-cell and macrophage progeny from AIDS virus infection.
Transduction of hematopoietic stem cells with genes that inhibit human immunodeficiency virus (HIV) replication has the potential to reconstitute immune function in individuals with AIDS. We evaluated the ability of an autoregulated gene, antitat, to inhibit replication of simian immunodeficiency virus (SIV) and HIV type 1 (HIV-1) in hematopoietic cells derived from transduced progenitor cells. The antitat gene expresses an antiviral RNA encoding polymeric Tat activation response elements in combination with an antisense tat moiety under the control of the HIV-1 long terminal repeat. CD34+ hematopoietic progenitor cells were transduced with a retroviral vector containing the antitat gene and then cultured under conditions that support in vitro differentiation of T cells or macrophage-like cells. Rhesus macaque CD4+ T cells and macrophage-like cells derived from CD34+ bone marrow cells transduced with the antitat gene were highly resistant to challenge with SIV, reflecting a 2- to 3-log reduction in peak SIV replication compared with controls. Similarly, human CD4+ T cells derived from CD34+ cord blood cells transduced with antitat were also resistant to infection with HIV-1. No evidence for toxicity of the antitat gene was observed in any of five different lineages derived from transduced hematopoietic cells. These results demonstrate that a candidate therapeutic gene introduced into hematopoietic progenitor cells can retain the ability to inhibit AIDS virus replication following T-cell differentiation and support the potential use of the antitat gene for stem cell gene therapy.
Rosenzweig
M
M
New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA.
Marks
D F
DF
Hempel
D
D
Lisziewicz
J
J
Johnson
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RP
D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002454:Cell Differentiation; D015683:Gene Products, gag / Q000032:analysis; D015696:Gene Products, tat / Q000235:genetics*; D005822:Genetic Vectors; D016655:HIV Core Protein p24 / Q000032:analysis; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000821:virology; D006801:Humans; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D012190:Retroviridae / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology*; D014170:Transformation, Genetic; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D018952:Antigens, CD34; C066594:Gag protein p27, Simian immunodeficiency virus; D015683:Gene Products, gag; D015696:Gene Products, tat; D016655:HIV Core Protein p24; D054322:tat Gene Products, Human Immunodeficiency Virus