Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lentiviral vectors modified from human immunodeficiency virus type 1 (HIV-1) offer a promising approach for gene therapy, facilitating transduction of genes into non-dividing cells both in vitro and in vivo. When transducing cytotoxic or anti-HIV genes, however, the vector must avoid self-inhibition by the transgene that can lead to a disruption in production of infectious virions. In this study, we constructed two HIV-1-based lentiviral vectors harboring the mifepristone-inducible gene expression unit in either the forward or the reverse orientation with respect to the direction of viral genomic RNA. The ability of these vectors to transduce cytotoxic and anti-HIV genes was evaluated. When human CD14 was used as a transgene, infectious lentiviral vectors were produced by both forward and reverse vector systems. CD14 expression was efficiently induced in cells transduced by both lentiviral vectors following treatment with mifepristone. However, a higher level of basal transgene expression was observed in the forward vector system in the absence of mifepristone. In contrast, high titers of infectious lentiviral vector containing the cytotoxic vesicular stomatitis virus M gene were successfully generated using the reverse vector, but not the forward vector. In addition, when a VPS4Bdominant negative mutant against HIV-1 budding was cloned into the reverse vector, significant amounts of lentiviral vector were obtained. Subsequent transduction of cells with the VPS4B mutant resulted in approximately 50% inhibition of HIV-1 production only in the presence of mifepristone. Our study thus demonstrates that incorporation of a mifepristone-regulatable gene expression unit in the reverse orientation makes significant advances toward development of a lentiviral vector that allows transduction of harmful genes.
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PMID:Efficient transduction of cytotoxic and anti-HIV-1 genes by a gene-regulatable lentiviral vector. 1955 42

Animal cells bud exosomes and microvesicles (EMVs) from endosome and plasma membranes. The combination of higher-order oligomerization and plasma membrane binding is a positive budding signal that targets diverse proteins into EMVs and retrovirus particles. Here we describe an inhibitory budding signal (IBS) from the human immunodeficiency virus (HIV) Gag protein. This IBS was identified in the spacer peptide 2 (SP2) domain of Gag, is activated by C-terminal exposure of SP2, and mediates the severe budding defect of p6-deficient and PTAP-deficient strains of HIV. This IBS also impairs the budding of CD63 and several other viral and nonviral EMV proteins. The IBS does not prevent cargo delivery to the plasma membrane, a major site of EMV and virus budding. However, the IBS does inhibit an interaction between EMV cargo proteins and VPS4B, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. Taken together, these results demonstrate that inhibitory signals can block protein and virus budding, raise the possibility that the ESCRT machinery plays a role in EMV biogenesis, and shed new light on the role of the p6 domain and PTAP motif in the biogenesis of HIV particles.
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PMID:Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins. 2124 5