Gene Therapy for AIDS Using Retroviral Mediated Gene Transfer to Deliver HIV-1 Antisense TAR and Transdominant Rev Protein Genes to Syngeneic Lymphocytes in HIV-1 Infected Identical Twins. National Institutes of Health, Bethesda, Maryland

Morgan, Richard A.; Walker, Robert

doi:10.1089/hum.1996.7.10-1281

Cited by 63 publications

(31 citation statements)

References 32 publications

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“…We wanted to overcome the safety problems associated with replication-competent viruses, so we decided to use a replicationdefective HIV-1 vector as a source of antigens. Replicationdefective retroviruses have been used as vectors for delivering therapeutic genes in experimental human gene therapy protocols and proved to be safe in HIV-1-infected patients but have not been shown to be effective in raising immune responses (27,35). We mutated the integrase gene of HIV-1 because integrase-mutant retroviruses are not only replication defective but also unable to introduce permanent genetic modification in infected cells (28,44).…”

Section: Resultsmentioning

confidence: 99%

Induction of Potent Human Immunodeficiency Virus Type 1-Specific T-Cell-Restricted Immunity by Genetically Modified Dendritic Cells

Lisziewicz

Gabrilovich

Varga

et al. 2001

J Virol

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A novel technology combining replication-and integration-defective human immunodeficiency virus type 1 (HIV-1) vectors with genetically modified dendritic cells was developed in order to induce T-cell immunity. We introduced the vector into dendritic cells as a plasmid DNA using polyethylenimine as the gene delivery system, thereby circumventing the problem of obtaining viral vector expression in the absence of integration. Genetically modified dendritic cells (GMDC) presented viral epitopes efficiently, secreted interleukin 12, and primed both CD4؉ and CD8 ؉ HIV-specific T cells capable of producing gamma interferon and exerting potent HIV-1-specific cytotoxicity in vitro. In nonhuman primates, subcutaneously injected GMDC migrated into the draining lymph node at an unprecedentedly high rate and expressed the plasmid DNA. The animals presented a vigorous HIV-specific effector cytotoxic-T-lymphocyte (CTL) response as early as 3 weeks after a single immunization, which later developed into a memory CTL response. Interestingly, antibodies did not accompany these CTL responses, indicating that GMDC can induce a pure Th1 type of immune response. Successful induction of a broad and long-lasting HIV-specific cellular immunity is expected to control virus replication in infected individuals.

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Section: Resultsmentioning

confidence: 99%

Induction of Potent Human Immunodeficiency Virus Type 1-Specific T-Cell-Restricted Immunity by Genetically Modified Dendritic Cells

Lisziewicz

Gabrilovich

Varga

et al. 2001

J Virol

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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%

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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“…Gene therapy clinical trials have demonstrated that infusion of transduced T cells does not cause any apparent adverse side-effects, and that the transduced T cells can survive in vivo for many months. [31][32][33] T cells transduced with an anti-HIV-1 gene M10 appeared to have a survival advantage in vivo compared with controls. 31 Genetically marked T cells were also found not only to persist in vivo for weeks to months, but also to expand in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 99%

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

Schroers

et al. 2002

Gene Ther

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Intrakines, modified intracellular chemokines, offer a novel strategy to prevent cellular entry of HIV-1 by blocking the surface expression of HIV-1 co-receptors. To investigate potential clinical applications of the RANTES-intrakine, we explored the use of HIV-1-based lentiviral vectors for therapeutic gene transfer into T-lymphocytes. RANTES-intrakine genes can be efficiently transduced into primary human Tlymphocytes by lentiviral vectors, especially when human Tlymphocytes were stimulated with CD3 and CD28 antibodies. The transduced T cells showed decreased surface expression of the chemokine receptor CCR-5, as well as CCR-1 and CCR-3. This lentivirus-mediated approach to

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Gene Therapy for AIDS Using Retroviral Mediated Gene Transfer to Deliver HIV-1 Antisense TAR and Transdominant Rev Protein Genes to Syngeneic Lymphocytes in HIV-1 Infected Identical Twins. National Institutes of Health, Bethesda, Maryland

Cited by 63 publications

References 32 publications

Induction of Potent Human Immunodeficiency Virus Type 1-Specific T-Cell-Restricted Immunity by Genetically Modified Dendritic Cells

Induction of Potent Human Immunodeficiency Virus Type 1-Specific T-Cell-Restricted Immunity by Genetically Modified Dendritic Cells

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

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

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