Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells

Greg M. Podsakoff, Barbara C. Engel, Denise A. Carbonaro, Chris Choi, Elzbieta M. Smogorzewska, Gerhard Bauer, David Selander, Susan Csik, Kathy Wilson, Michael R. Betts, Richard A. Koup, Gary J. Nabel, Keith Bishop, Steven King, Manfred Schmidt, Christof von Kalle, Joseph A. Church, Donald B. Kohn

Research output: Contribution to journalArticle

62 Citations (Scopus)

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 0antiretroviral 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.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalMolecular Therapy
Volume12
Issue number1
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Bone Marrow Cells
HIV-1
HIV
Lymphocytes
Genes
Blood Cells
Hematopoietic Stem Cells
Bone Marrow
Polymerase Chain Reaction
Viral Load
Limit of Detection
Clone Cells
Survival

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells. / Podsakoff, Greg M.; Engel, Barbara C.; Carbonaro, Denise A.; Choi, Chris; Smogorzewska, Elzbieta M.; Bauer, Gerhard; Selander, David; Csik, Susan; Wilson, Kathy; Betts, Michael R.; Koup, Richard A.; Nabel, Gary J.; Bishop, Keith; King, Steven; Schmidt, Manfred; von Kalle, Christof; Church, Joseph A.; Kohn, Donald B.

In: Molecular Therapy, Vol. 12, No. 1, 07.2005, p. 77-86.

Research output: Contribution to journalArticle

Podsakoff, GM, Engel, BC, Carbonaro, DA, Choi, C, Smogorzewska, EM, Bauer, G, Selander, D, Csik, S, Wilson, K, Betts, MR, Koup, RA, Nabel, GJ, Bishop, K, King, S, Schmidt, M, von Kalle, C, Church, JA & Kohn, DB 2005, 'Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells', Molecular Therapy, vol. 12, no. 1, pp. 77-86. https://doi.org/10.1016/j.ymthe.2005.02.024
Podsakoff, Greg M. ; Engel, Barbara C. ; Carbonaro, Denise A. ; Choi, Chris ; Smogorzewska, Elzbieta M. ; Bauer, Gerhard ; Selander, David ; Csik, Susan ; Wilson, Kathy ; Betts, Michael R. ; Koup, Richard A. ; Nabel, Gary J. ; Bishop, Keith ; King, Steven ; Schmidt, Manfred ; von Kalle, Christof ; Church, Joseph A. ; Kohn, Donald B. / Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells. In: Molecular Therapy. 2005 ; Vol. 12, No. 1. pp. 77-86.
@article{bfb39dcd747341d1933badd0f4db0984,
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 0antiretroviral 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.",
author = "Podsakoff, {Greg M.} and Engel, {Barbara C.} and Carbonaro, {Denise A.} and Chris Choi and Smogorzewska, {Elzbieta M.} and Gerhard Bauer and David Selander and Susan Csik and Kathy Wilson and Betts, {Michael R.} and Koup, {Richard A.} and Nabel, {Gary J.} and Keith Bishop and Steven King and Manfred Schmidt and {von Kalle}, Christof and Church, {Joseph A.} and Kohn, {Donald B.}",
year = "2005",
month = "7",
doi = "10.1016/j.ymthe.2005.02.024",
language = "English (US)",
volume = "12",
pages = "77--86",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34+ cells

AU - Podsakoff, Greg M.

AU - Engel, Barbara C.

AU - Carbonaro, Denise A.

AU - Choi, Chris

AU - Smogorzewska, Elzbieta M.

AU - Bauer, Gerhard

AU - Selander, David

AU - Csik, Susan

AU - Wilson, Kathy

AU - Betts, Michael R.

AU - Koup, Richard A.

AU - Nabel, Gary J.

AU - Bishop, Keith

AU - King, Steven

AU - Schmidt, Manfred

AU - von Kalle, Christof

AU - Church, Joseph A.

AU - Kohn, Donald B.

PY - 2005/7

Y1 - 2005/7

N2 - 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 0antiretroviral 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.

AB - 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 0antiretroviral 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.

UR - http://www.scopus.com/inward/record.url?scp=20844440241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20844440241&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2005.02.024

DO - 10.1016/j.ymthe.2005.02.024

M3 - Article

VL - 12

SP - 77

EP - 86

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 1

ER -