INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS-1 (HIV-1) REPLICATION AFTER TRANSDUCTION OF GRANULOCYTE-COLONY-STIMULATING FACTOR-MOBILIZED CD34(-1-INFECTED DONORS USING RETROVIRAL VECTORS CONTAINING ANTI-HIV-1 GENES() CELLS FROM HIV)

Transfer of ''anti-HIV-1 genes'' into hematopoietic stem cells of huma n immunodeficiency virus-1 (HIV-1)-infected individuals may be a poten t therapeutic approach to render mature cells arising from transduced stem cells resistant to the destructive events associated with HIV-1 i nfection. To determine the feasibility of gene therapy for acquired im munodeficiency syndrome in individuals already infected with HIV-1, gr anulocyte colony-stimulating factor mobilized peripheral blood CD34(+) cells were isolated from HIV-1-infected individuals and transduced wi th retroviral vectors containing three different anti-HIV-1-genes: the Rev binding domain of the Rev Responsive Element (RRE decoy) (L-RRE-n eo), a double hammerhead ribozyme vector targeted to cleave the tar an d rev transcripts (L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a control, a vector mediating only neomycin resi stance (LN) was used. After 3 days of transduction on allogeneic strom a in the presence of stem cell factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected, and then challenged with HIV-1(JR-FL ) and a primary HIV-1 isolate. Compared with the control cultures, the L-RRE-neo-, L-TR/TAT-neo-, and L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1 replication after challenge with HIV-1(JR-FL) and the primary HIV-1 isolate. Growth of the hematopoiet ic cells in long-term bone marrow culture was not perturbed by the pre sence of any of the anti-HIV-l genes. This study shows that anti-HIV-1 genes can be introduced into CD34(+) cells from individuals already i nfected with HIV-1, and strongly inhibit HIV-1 replication in primary monocytes derived from the CD34(+) progenitors. (C) 1997 by The Americ an Society of Hematology.