Hematologic Recovery in Mice Transplanted with Bone Marrow Stem Cells Expressing Anti-Human Immunodeficiency Virus Genes

Morel, Franck; Salimi, Suzan; Markovits, Judith; Austin, Timothy W.; Plavec, Ivan

doi:10.1089/10430349950016519

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…The erythroid hematopoietic compartment was made up exclusively of cells of donor origin. These results are comparable with the relative distribution of cells of hematopoietic lineage in peripheral blood of control mice reported by Morel et al [26]. Thus, the results indicate that our Sca-1+ cell transplantation strategy could lead to multilineage hematopoietic cell engraftment.…”

Section: Resultssupporting

confidence: 91%

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

et al. 2006

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This study sought to develop a murine bone marrow transplantation strategy that would yield consistently high levels of long-term engraftment without significant morbidity and mortality. Hematopoietic stem cell (HSC)-enriched Sca-1+ cells were used for transplantation because of their propensity of homing to bone marrow. Green fluorescent protein (GFP)-expressing transgenic mice were used as donors. Murine Sca-1+ cells were enriched 13-fold from whole bone marrow with immunomagnetic column chromatography. Retroorbital injections yielded highly reproducible and higher levels of engraftment compared with tail vein injections. The combination of W⁴¹/W⁴¹ recipient mice and sublethal irradiation preconditioning produced long-term engraftment with minimal morbidity and mortality. A 24-hour delay between the sublethal irradiation and transplantation did not affect the efficiency and level of engraftment, but provided flexibility with respect to the timing of transplantation. Based on these findings, a mouse Sca-1+ cell-based strategy, involving the retroorbital injection of Sca-1+ cells into sublethally irradiated, myelosuppressed W⁴¹/W⁴¹ recipient mice within 24 h after irradiation, was developed. Transplantation of lentiviral vector-transduced wild-type Sca-1+ cells expressing GFP by this strategy led to consistently high levels of long-term engraftment. In summary, this murine Sca-1+ cell-based strategy could be used in studies of HSC-based gene or cell therapies.

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Section: Resultssupporting

confidence: 91%

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

et al. 2006

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“…1B). In these experiments, we observed an increase in the SϩG 2 /M percent in all cell types examined, but a particularly higher level of SϩG 2 /M cells was detected in the Ter-119 ϩ erythroid population (33) and the Gr1 ϩ population containing granulocytes plus monocytes (31,46). Consistent with this, we also detected a significant increase in cell number in all splenic cell types, but the increases in the Ter-119 ϩ and Gr1 ϩ cell populations were again the most dramatic (Fig.…”

Section: Increase In Cell Cycle Entry and Cell Number Of P27mentioning

confidence: 61%

p27^Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo

Soeiro

Mohamedali

Romańska

et al. 2006

Molecular and Cellular Biology

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To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27 Kip1؊/؊ ; p130 ؊/؊ mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27 Kip1؊/؊ counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27 Kip1؊/؊ ; p130 ؊/؊ animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1؊/؊ splenocytes. The finding that the p27 Kip1؊/؊ ; p130 ؊/؊ splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.For mammalian cells to duplicate, they have to progress through a series of processes that comprise the cell cycle. The retinoblastoma protein (pRB) pathway (i.e., cyclins, CDKs, CDK-inhibitors [CKIs], pRB, and E2F) links the positive and negative proliferative signals to the cell cycle machinery, and this pathway is inactivated in the majority of human cancers (37, 38). Mammalian cells become growth factor independent after passing the restriction point within the G 1 phase of the cell cycle (34). Two families of G 1 cyclins, D-type cyclins (cyclin D1, D2, and D3) and cyclin E (cyclin E1 and E2) (37), and their dependent kinases (CDK4, -6, and -2) control the transition through G 1 into the S phase of the cell cycle. The principal cellular targets of the G 1 cyclin-dependent CDKs are the pRB family of pocket proteins, consisting of pRB, p107, and p130. In quiescent cells, hypophosphorylated forms of the pRB-related pocket proteins associate with members of the E2F family of transcription factors, thereby negatively regulating the transcriptional activity of E2F-regulated genes, whose products are important for entry into S phase and DNA syn-

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“…Several strategies have been employed, including targeting of the HIV coreceptor to prevent infection and spread (21), inhibition of regulatory genes like the packaging sequence, tar, and primer binding site (6), or targeting of structural or nonstructural viral gene products like rev, envelope, virulence factors, etc. (6,10,19,26,27,40,44,47). Importantly, the ability of antisense to inhibit HIV replication in vivo was demonstrated in a monkey model given autologous T cells modified with a vector containing antisense against the tat/rev gene prior to challenge (10).…”

Section: Discussionmentioning

confidence: 99%

“…Efficacy can also be improved after dosing of the patient by using a selection gene to increase the number of vector-modified cells in vivo (9). An alternative approach would be to transduce stem cells that have the ability to mature into virus-resistant lymphocytes (9,26).…”

Section: Discussionmentioning

confidence: 99%

Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance

Lü

Qiao

Binder

et al. 2004

J Virol

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We have constructed a human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector expressing a 937-base antisense sequence against the HIV-1 envelope gene. Transduction of CD4 ؉ T lymphocytes with this vector results in expression of the therapeutic antisense sequence and subsequent inhibition of productive HIV-1 replication. In this report, we examined the effect of antisense-mediated suppression on the potential development of virus escape mutants using a permissive T-cell line cultured under conditions that over serial passages specifically allowed for generation and amplification of mutants selected for by antisense pressure. In the resulting virus clones, we found a significant increase in the number of deletions at the envelope target region (91% compared to 27.5% in wild-type HIV). Deletions were most often greater than 1 kb in length. These data demonstrate for the first time that during antisense-mediated suppression of HIV, mutants develop as a direct result of selective pressure on the HIV genomic RNA. Interestingly, in clones where deletions were not observed, there was a high rate of A-G transitions in mutants at the antisense target region but not outside this region, which is consistent with those mutations that are predicted as a result of antisense-mediated modification of double-stranded RNA by the enzyme double-stranded RNA-specific adenosine deaminase. These clones were not found to be escape mutants, as their replicative ability was severely attenuated, and they did not replicate in the presence of vector.

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Hematologic Recovery in Mice Transplanted with Bone Marrow Stem Cells Expressing Anti-Human Immunodeficiency Virus Genes

Cited by 7 publications

References 24 publications

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

p27^Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo

Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance

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Hematologic Recovery in Mice Transplanted with Bone Marrow Stem Cells Expressing Anti-Human Immunodeficiency Virus Genes

Cited by 7 publications

References 24 publications

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

An Improved Mouse Sca-1+ Cell-Based Bone Marrow Transplantation Model for Use in Gene- and Cell-Based Therapeutic Studies

p27Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo

Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance

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p27^Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo