Gene therapy targeting cord blood-derived CD34+ cells from HIV-exposed infants: preclinical studies

Li, X; Gervaix, Alain; Kang, David E.; Law, Ping; Spector, Stephen A.; Ho, A. D.; Wong‐Staal, Flossie

doi:10.1038/sj.gt.3300582

Cited by 32 publications

(19 citation statements)

References 10 publications

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“…49 Progenitor cell gene therapy for HIV-infected infants before the immune system is severely compromised has been suggested. 50 The ultimate goal of gene therapy would be to reconstitute the immune system with genetically altered cells that are resistant to HIV. However, if there were intrinsic functional defects in CD34 ϩ cells from HIV-exposed or infected infants, such a strategy would not succeed.…”

Section: Discussionmentioning

confidence: 99%

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

Nielsen

Jeppesen

Kolte

et al. 2001

Blood

119

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Hematologic and immunologic functions were examined in 19 HIV-negative infants of HIV-positive mothers and 19 control infants of HIV-negative mothers. Control infants were selected to match for gestational age, weight, and mode of delivery. Cord blood was obtained from all infants and used for flow cytometric determination of lymphocyte subsets, including the naive CD4 count. Furthermore, to determine thymic output, cord blood mononuclear cells were used for determination of T-cell receptor excision circles (TRECs). Evaluation of progenitor cell function was IntroductionVertical transmission of HIV from an HIV-positive mother to her infant occurs in 15% to 25% of pregnancies if no precautions are taken. However, the risk of vertical transmission of HIV has been dramatically reduced with the introduction of antiretroviral treatment in combination with delivery by elective cesarean section and avoidance of breastfeeding. 1,2 Although infants of HIV-positive mothers are rarely HIVinfected, they may have been exposed to HIV proteins or even HIV particles during fetal life, as indicated by the presence of HIV-specific T cells, immune activation, and positive HIV polymerase chain reaction (PCR) found in HIV-exposed infants. [3][4][5][6][7] Thus, a recent study demonstrated high frequencies of HIV-specific CD4 ϩ cells and a lower frequency of HIV-specific CD8 ϩ cells, indicating transplacental diffusion of HIV-soluble proteins. 8 HIV particles as well as HIV proteins are known to inhibit progenitor cell function and to cause progenitor cell apoptosis which, in turn, would lead to both hematologic and immunologic deficiencies in the infants. [9][10][11][12][13][14][15][16][17][18] Furthermore, cytokine imbalance between Th1-and Th2-type cytokines has been suggested in HIV-positive individuals. [19][20][21] Such an imbalance in pregnant HIV-positive women might also cause cytokine imbalance in the fetus, resulting in immunologic deficiencies. Finally, pregnant HIV-positive women are commonly treated with antiretroviral therapy including zidovudine (AZT), and AZT is known to inhibit bone marrow functions. 22 The present study was conducted to determine if HIV-negative infants of HIV-positive mothers have immune deficiencies as determined by CD4 and CD8 counts in cord blood. Furthermore, thymic output was evaluated by determination of CD4 ϩ and CD8 ϩ cells with naive phenotype (coexpression of CD45RA) and determination of T-cell receptor excision circles (TRECs). Evidence of reduced thymic output was found and, to determine if impaired progenitor cell function might contribute to this, colony-forming cell (CFC) assays were performed to examine the function of myeloid progenitors, and fetal thymic organ cultures (FTOCs) were done to examine the function of T-cell progenitors. Recently, correlation between lymphocyte proliferation and expression of the early activation marker CD69 has been shown. 23,24 To determine if immune activation in infants of HIV-positive mothers might contribute to the lower level of naive CD4 ϩ cel...

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Section: Discussionmentioning

confidence: 99%

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

Nielsen

Jeppesen

Kolte

et al. 2001

Blood

119

View full text Add to dashboard Cite

show abstract

“…This approach has shown to inhibit HIV replication in vitro and prolong T cell survival in vivo. [1][2][3][4][5][6][7][8] The use of HIV-based conditionally replicating vectors expressing anti-HIV genes for the treatment of AIDS offers several theoretical advantages over the MoMLVbased vector systems. Unlike MoMLV, lentiviral vectors can effectively transduce both dividing and non-dividing cells such as resting T cells, macrophages or dendritic cells, 9,10 which may play an important role in the maintenance of HIV-1 infection.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV-1 replication by novel lentiviral vectors expressing transdominant Rev and HIV-1 env antisense

2002

Gene Ther

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“…[1][2][3][4] Their extensive ability to proliferate and self-renew make them an attractive target for gene therapy. [5][6][7] Peripheral blood progenitor cells (PBPCs) are a clinically relevant stem cell source and can be obtained from patients in ample quantity. 8,9 Their transduction with retroviral vectors has been optimized so that high levels of gene transfer can be achieved.…”

Section: Introductionmentioning

confidence: 99%

Retroviral vector integration occurs in preferred genomic targets of human bone marrow-repopulating cells

Laufs

Gentner

Nagy

et al. 2002

Blood

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Increasing use of hematopoietic stem cells for retroviral vector-mediated gene therapy and recent reports on insertional mutagenesis in mice and humans have created intense interest to characterize vector integrations on a genomic level. We studied retrovirally transduced human peripheral blood progenitor cells with bone marrow-repopulating ability in immune-deficient mice. By using a highly sensitive and specific ligation-mediated polymerase chain reaction (PCR) followed by sequencing of vector integration sites, we found a multitude of simultaneously active human stem cell clones 8 weeks after transplantation. Vector integrations occurred with significantly increased frequency into chromosomes 17 and 19 and into specific regions of chromosomes 6, 13, and 16, although most of the chromosomes were targeted. Preferred genomic target sites have previously only been reported for wild-type retroviruses. Our findings reveal for the first time that retroviral vector integration into human marrow-repopulating cells can be nonrandom (P ‫؍‬ .000 37). (Blood. 2003;

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Gene therapy targeting cord blood-derived CD34+ cells from HIV-exposed infants: preclinical studies

Cited by 32 publications

References 10 publications

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

Inhibition of HIV-1 replication by novel lentiviral vectors expressing transdominant Rev and HIV-1 env antisense

Retroviral vector integration occurs in preferred genomic targets of human bone marrow-repopulating cells

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