TRANSDUCTION OF CD34(-CELL AND MACROPHAGE PROGENY FROM AIDS VIRUS-INFECTION() HEMATOPOIETIC PROGENITOR CELLS WITH AN ANTITAT GENE PROTECTS T)

Transduction of hematopoietic stem cells with genes that inhibit human immunodeficiency virus (HIV) replication has the potential to reconst itute immune function in individuals with AIDS. We evaluated the abili ty 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 expre sses an antiviral RNA encoding polymeric Tat activation response eleme nts in combination with an antisense tat moiety under the control of t he HIV-1 long terminal repeat. CD34(+) hematopoietic progenitor cell w ere transduced with a retroviral vector containing the antitat gene an d then cultured under conditions that support in vitro differentiation of T cells or macrophage-like cells. Rhesus macaque CD4(+) T cells an ti macrophage-like cells derived from CD34(+) bone marrow cells transd uced with the antitat gene Here 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(+) co rd blood cells transduced with antitat were also resistant to infectio n with HIV-1. No evidence for toxicity of the antitat gene was observe d in any of five different lineages derived from transduced hematopoie tic 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 an d support the potential use of the antitat gene for stem cell gene the rapy.