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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic stem cells (HSC) require extensive cytokine-mediated stimulation and proliferation for efficient transduction by oncoretroviral vectors. Since lentiviral vectors can transduce nondividing cells, the need for cytokine stimulation has been questioned. We studied HIV-based lentiviral transduction of human early hematopoietic progenitors from umbilical cord blood in the presence or absence of IL-3, IL-6, stem cell factor (SCF), and Flt-3L (36SF) or SCF alone and characterized the effects of these conditions on the stem cell phenotype. Gene transfer was significantly higher in the presence of 36SF in mass culture cells, CFC, LTCIC, and NOD/SCID repopulating cells (SRC). Transduction of primitive progenitor/stem cells was poor without cytokines, with only 12% LTCIC and 23% SRC transduced, compared to 59% in LTCIC and 81% in SRC with 36SF. SCF alone matched transduction rates of multiple cytokines with 70% in CFC. Cytokines prevented apoptosis, expanded CD34(+) cell number, and maintained CFC and LTCIC frequencies. Cytokine stimulation increased transduction of nondividing Ara-C-resistant and aphidicolin-inhibited cells similar to dividing cells. These data suggest that cytokines enhance lentiviral transduction of HSC, without requiring cell division, and maintain the stem cell phenotype. SCF stimulation alone was sufficient for high level transduction.
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PMID:Cytokines, including stem cell factor alone, enhance lentiviral transduction in nondividing human LTCIC and NOD/SCID repopulating cells. 1266 28

Dendritic cells hold promise as adjuvant for immunotherapy for cancer and infectious diseases. We demonstrate that a significant number of cryopreserved peripheral blood CD34(+) cells from HIV-infected subjects can be transduced with a replication-incompetent lentiviral vector expressing HIV antigens. In addition, untransduced and transduced CD34(+) cells from HIV-infected individuals were able to differentiate into dendritic cells with strong T-cell stimulatory capacity. Thus, cryopreserved CD34(+) cells from HIV-infected subjects may prove useful for immunotherapy for HIV/AIDS.
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PMID:Generation of dendritic cells from lentiviral vector-transduced CD34+ cells from HIV+ donors. 1269 3

The use of recombinant vectors based on wild-type viruses that are absent in humans and are not associated with any disease in their natural animal hosts or in accidentally infected humans would add an additional level of safety for human somatic gene therapy approaches. These criteria are fulfilled by foamy viruses (FVs), a family of complex retroviruses whose members are widely found among mammals and are apathogenic in all hosts. Here, we show by comparison of identically designed vector constructs that recombinant retroviral vectors based on FVs were as efficient as lentiviral vectors in transducing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice repopulating human CD34(+) cord blood (CB) cells. The FV vector was able to achieve gene transfer levels up to 84% of engrafted human cells in a short overnight transduction protocol. In contrast, without prestimulation of the target cells, a human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector pseudotyped with gibbon ape leukemia virus envelope (GALV Env) was nearly as inefficient as murine leukemia virus (MLV)-based oncoretroviral vectors in transducing NOD/SCID repopulating cells. The same HIV vector pseudotyped with the vesicular stomatitis virus glycoprotein G (VSV-G) achieved high marking efficiency. Clonality analysis of bone marrow samples showed oligoclonal hematopoiesis with single to multiple insertions per cell, both for FV and HIV vectors. These data demonstrate that vectors based on FVs warrant further investigation and development for medical use.
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PMID:Comparison of three retroviral vector systems for transduction of nonobese diabetic/severe combined immunodeficiency mice repopulating human CD34+ cord blood cells. 1271 62

The phenomenon of RNA interference mediated by small interfering RNAs (siRNAs) is a potent gene-silencing mechanism. A number of recent studies demonstrated inhibition of HIV-1 replication in cultured cells using this approach. To make further progress and harness this technology for HIV-1 gene therapy in a stem cell setting, in vivo studies using primary hematopoietic cells are needed. Using an HIV-based lentiviral vector we introduced an anti-Rev siRNA construct into CD34(+) hematopoietic progenitor cells. The siRNA-transduced progenitor cells were allowed to mature into macrophages in vitro and T cells in vivo in SCID-hu mouse thy/liv grafts. Phenotypically normal T cells and macrophages displaying characteristic surface markers were obtained. In vitro HIV-1 challenge of the siRNA-expressing macrophages and T cells with macrophage-tropic and T-cell-tropic HIV-1, respectively, showed marked viral resistance. These experiments demonstrate the utility of siRNAs delivered into hematopoietic stem cells via lentiviral vectors for future in vivo applications.
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PMID:Inhibition of HIV-1 by lentiviral vector-transduced siRNAs in T lymphocytes differentiated in SCID-hu mice and CD34+ progenitor cell-derived macrophages. 1284 29

IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34(+) subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34(high)CD5(+)CD1a(-) thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4(+)CD8(+) thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4(+)CD3(+)CD8(-) and CD8(+)CD3(+)CD4(-) thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.
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PMID:Effects of IL-7 on early human thymocyte progenitor cells in vitro and in SCID-hu Thy/Liv mice. 1284 29

In order to assess immune responses during HIV-1 therapeutic immunization, a large number of blood mononuclear cells (PBMC) are needed. Clinical tolerance and safety, as well as changes in immunological and virological parameters, were assessed, following leukapheresis in HIV-1 infected subjects with CD4(+) cell count >200 x 10(6)/l. PBMC were collected using a Fenwal CS3000 cell separator in 29 subjects with mean CD4(+) cell counts of 503 x 10(6)/l (range 172-1,119) and viral load of 2.5 log(10) copies/ml (range <1.7-5.4). Twenty-four (83%) subjects were on antiretroviral therapy while 5 (17%) were untreated. The blood volume processed was 7 L over a period of 3 hours. A mean value (+/- standard error) of 82 +/- 26 x 10(9)/l lymphocytes was collected by a single apheresis in a mean volume of 200 +/- 1.8 ml, containing 9.0 +/- 1.3 x 10(9)/l CD4(+) and 10.2 +/- 1.3 x 10(9)/l CD8(+) cells. The leukapheresis procedures were well tolerated and no immediate or delayed side effects were observed within 90 days of follow-up. No changes from blood pre-leukapheresis values were detected for white blood cells, lymphocytes, monocytes, CD8(+), CD34(+), naive and memory CD4(+) cell counts immediately after, 1 h, 7 days, or within 90 days after leukapheresis. However, absolute CD4(+) cell counts and percentage significantly increased from pre-leukapheresis values after 1 h (530 +/- 43 vs. 700 +/- 75 cell x 10(6)/l; 32.6 +/- 1.6 vs. 36.9 +/- 1.9%; P < 0.001 for both paired t-tests) before returning to pre-leukapheresis levels on day 7. No significant changes in viral load from pre-leukapheresis levels in treated or untreated subjects were detected at any time points. We conclude that leukapheresis in HIV-1 infected subjects with CD4(+) cell counts >200 x 10(6)/l is safe and induces a transient increase in the absolute and percentage of CD4(+) cell count without enhancing viral replication.
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PMID:Changes in immunological and virological parameters in HIV-1 infected subjects following leukapheresis. 1287 16

Gene therapy strategies for HIV infection require gene transduction of hematopoietic stem cells with effective therapeutic constructs. Here we summarize our studies on anti-HIV ribozymes, RNA decoys and the newly described siRNAs. The therapeutic constructs consisted of an anti-CCR5 ribozyme to down-regulate the HIV-1 cell surface co-receptor and ribozymes targeted to viral mRNAs coding for the tat, rev and env proteins. The RNA decoy targeted rev and the siRNA was directed against a sequence common to rev and tat mRNAs. CD34 hematopoietic progenitor cells were transduced with retroviral or lentiviral vectors containing these constructs. They were differentiated into macrophages in vitro and T cells in vivo in a SCID-hu mouse thymopoiesis model. The transgene-containing macrophages and T cells were found to be phenotypically normal. When challenged in vitro with HIV-1, they showed significant anti-viral resistance. These proof-of-concept studies demonstrated the utility of RNA-based anti-HIV constructs for gene therapy.
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PMID:siRNAs, ribozymes and RNA decoys in modeling stem cell-based gene therapy for HIV/AIDS. 1289 72

Difficulty in gene transduction of human blood cells, including hematopoietic stem cells, has hampered the development of gene therapy applications for hematological disorders, encouraging the development and use of new gene delivery systems. In this study, we used a third-generation self-inactivating (SIN) lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) to improve transduction efficiency and prevent vector-related toxicity. The transduction efficiency of the HIV-1-based vector was compared directly with the Moloney murine leukemia virus (MLV) SIN vector in human leukemia cell lines. Initial transduction efficiencies were almost 100% for the HIV and less than 50% for the MLV vectors. Similar results were observed in 11 types of primary cells obtained from leukemia or myeloma patients. Transgene expression persisted for 8 weeks in cells transduced with the HIV vector, but declined with the MLV vector. In addition, resting peripheral blood lymphocytes and CD34(+) hematopoietic cells were transduced successfully with the HIV vector, but not with the MLV vector. Finally, we confirmed vector gene integration in almost all colony-forming cells transduced with the HIV vector, but not with the MLV vector. In conclusion, this lentiviral vector is an excellent gene transduction system for human blood cells because of its high gene transduction and host chromosome integration efficiency.
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PMID:Effective transduction and stable transgene expression in human blood cells by a third-generation lentiviral vector. 1290 Jul 59

A primary advantage of lentiviral vectors is their ability to pass through the nuclear envelope into the cell nucleus thereby allowing transduction of nondividing cells. Using HIV-based lentiviral vectors, we delivered an anti-CCR5 ribozyme (CCR5RZ), a nucleolar localizing TAR RNA decoy, or Pol III-expressed siRNA genes into cultured and primary cells. The CCR5RZ is driven by the adenoviral VA1 Pol III promoter, while the human U6 snRNA Pol III-transcribed TAR decoy is embedded in a U16 snoRNA (designated U16TAR), and the siRNAs were expressed from the human U6 Pol III promoter. The transduction efficiencies of these vectors ranged from 96-98% in 293 cells to 15-20% in primary PBMCs. A combination of the CCR5RZ and U16TAR decoy in a single vector backbone gave enhanced protection against HIV-1 challenge in a selective survival assay in both primary T cells and CD34(+)-derived monocytes. The lentiviral vector backbone-expressed siRNAs also showed potent inhibition of p24 expression in PBMCs challenged with HIV-1. Overall our results demonstrate that the lentiviral-based vectors can efficiently deliver single constructs as well as combinations of Pol III therapeutic expression units into primary hematopoietic cells for anti-HIV gene therapy and hold promise for stem or T-cell-based gene therapy for HIV-1 infection.
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PMID:Inhibition of HIV-1 infection by lentiviral vectors expressing Pol III-promoted anti-HIV RNAs. 1290 42

We report a 39-year-old HIV negative man with a solitary reddish-brown papule located on the glans penis, which had developed 6 months previously. Histopathologic examination showed spindle-shaped cells scattered between collagen bundles and intermingled with small, pointed vascular-like spaces. Spindle-shaped cells stained positively for antiFactor VIII and anti-CD34 antibodies. Human herpes virus-8 DNA was detected in tumor tissue and in peripheral blood mononuclear cells. Based on clinicopathologic and molecular findings, the diagnosis of classic Kaposi's sarcoma was made. Two months after the initial observation, three additional papules developed on the glans penis. Histopathologic examination of one lesion confirmed the diagnosis of classic Kaposi's sarcoma. The remaining lesions were treated with electrodessication and curettage. After a follow-up period of 6 months no evidence of recurrence was observed. We report this case for the unusual localization of Kaposi's Sarcoma in a young, HIV-negative patient.
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PMID:Kaposi's sarcoma of the glans penis in an immunocompetent patient. 1472 80


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