Inhibition of Human Immunodeficiency Virus Type 1 (HIV-1) Replication by HIV-1-Based Lentivirus Vectors Expressing Transdominant Rev
Open Access
- 15 April 2001
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 75 (8) , 3590-3599
- https://doi.org/10.1128/jvi.75.8.3590-3599.2001
Abstract
Retrovirus vectors expressing transdominant-negative mutants of Rev (TdRev) inhibit human immunodeficiency virus type 1 (HIV-1) replication by preventing the nuclear export of unspliced viral transcripts, thus inhibiting the synthesis of Gag-Pol, Env, and genomic RNA. The use of HIV-1–based vectors to express TdRev would have the advantage of allowing access to nondividing hematopoietic cells. It would also provide additional levels of protection by sequestering the viral regulatory proteins Tat and Rev, competing for encapsidation into wild-type virions, and inhibiting reverse transcription. Here we describe HIV-1-based vectors that express TdRev. These vectors contain mutations in the splicing signals or replacement of the Rev-responsive element by the simian retrovirus type 1 constitutive transport element, making them less sensitive to the inhibitory effects of TdRev. In addition, overexpression of Rev and the use of an HIV-1 helper plasmid that drives high levels of Gag-Pol synthesis were used to transiently overcome the inhibition by TdRev of the synthesis of Gag-Pol during vector production. SupT1 cells transduced with these vectors were more resistant to HIV-1 replication than cells transduced with Moloney murine leukemia virus-based vectors expressing TdRev. Furthermore, we show that these vectors can be mobilized by the wild-type virus, reducing the infectivity of virions escaping inhibition and conferring protection against HIV-1 replication to previously untransduced cells.Keywords
This publication has 29 references indexed in Scilit:
- Potent Inhibition of Human Immunodeficiency Virus Type 1 Replication by Conditionally Replicating Human Immunodeficiency Virus-Based Lentiviral Vectors Expressing Envelope Antisense mRNAHuman Gene Therapy, 2000
- Improved titers of HIV-based lentiviral vectors using the SRV-1 constitutive transport elementGene Therapy, 2000
- Modified Human Immunodeficiency Virus-Based Lentiviral Vectors Display Decreased Sensitivity toTrans-Dominant RevHuman Gene Therapy, 2000
- Inhibition of Human Immunodeficiency Virus Type 1 by Tat/Rev-Regulated Expression of Cytosine Deaminase, Interferon alpha2, or Diphtheria Toxin Compared with Inhibition by Transdominant RevHuman Gene Therapy, 1999
- Gene therapy targeting cord blood-derived CD34+ cells from HIV-exposed infants: preclinical studiesGene Therapy, 1998
- High transdominant RevM10 protein levels are required to inhibit HIV-1 replication in cell lines and primary T cells: implication for gene therapy of AIDSGene Therapy, 1997
- 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, MarylandHuman Gene Therapy, 1996
- Analysis oftrans-Dominant Mutants of the HIV Type 1 Rev Protein for Their Ability to Inhibit Rev Function, HIV Type 1 Replication, and Their Use as Anti-HIV Gene TherapeuticsAIDS Research and Human Retroviruses, 1995
- Inhibition of Human Immunodeficiency Virus Type-1 by Retroviral Vectors Expressing Antisense-TARHuman Gene Therapy, 1994
- Transfer of an Anti-HIV-1 Ribozyme Gene into Primary Human LymphocytesHuman Gene Therapy, 1994