title: Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34(+) cells.
abstract: Two HIV-1-infected children on antiretroviral therapy were enrolled into a clinical study of retroviral-mediated transfer of a gene that inhibits replication of HIV-1, targeting bone marrow CD34+ hematopoietic stem/progenitor cells. Two retroviral vectors were used, one encoding a "humanized" dominant-negative REV protein (huM10) that is a potent inhibitor of HIV-1 replication and one encoding a nontranslated marker gene (FX) to serve as an internal control for the level of gene marking. Peripheral blood mononuclear cells (PBMC) containing the huM10 gene or FX gene were detected by quantitative PCR at frequencies of approximately 1/10,000 in both subjects for the first 1-3 months following re-infusion of the gene-transduced bone marrow, but then were at or below the limits of detection (<1/1,000,000) at most times over 2 years. In one patient, a reappearance of PBMC containing the huM10 gene, but not the FX gene, occurred concomitant with a rise in the HIV-1 viral load during a period of nonadherence to the antiretroviral regimen. Unique clones of gene-marked PBMC were detected by LAM-PCR during the time of elevated HIV-1 levels. These findings indicate that there was a selective survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load.
authors.affiliation: Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Podsakoff
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Engel
authors.forename: Denise A
authors.initials: DA
authors.lastname: Carbonaro
authors.forename: Chris
authors.initials: C
authors.lastname: Choi
authors.forename: Elzbieta M
authors.initials: EM
authors.lastname: Smogorzewska
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauer
authors.forename: David
authors.initials: D
authors.lastname: Selander
authors.forename: Susan
authors.initials: S
authors.lastname: Csik
authors.forename: Kathy
authors.initials: K
authors.lastname: Wilson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Keith
authors.initials: K
authors.lastname: Bishop
authors.forename: Steven
authors.initials: S
authors.lastname: King
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Church
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000494:pharmacology; D005260:Female; D005819:Genetic Markers; D015316:Genetic Therapy; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; D005819:Genetic Markers; D004247:DNA