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A conditionally replicating HIV-based vector that stably expresses an antiviral shRNA against HIV-1 replication. 2006

Ellen M Westerhout, and Monique Vink, and P C Joost Haasnoot, and Atze T Das, and Ben Berkhout
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.

Human pathogenic viruses can be targeted by therapeutic strategies based on RNA interference. Whereas the administration of synthetic short interfering RNAs (siRNAs) may transiently inhibit viral replication, long-term inhibition may be achieved through stable intracellular expression of siRNAs or short hairpin RNAs (shRNAs). Both approaches face serious problems with delivery to the right cells in an infected individual. We explored the potential of a replicating HIV-based vector to deliver an antiviral shRNA cassette into HIV-1-susceptible target cells to block chronic HIV-1 infection. The vector is based on a doxycycline (dox)-dependent HIV-1 variant that we previously proposed as a conditional-live HIV-1 vaccine. With dox, this virus spreads efficiently to all HIV-susceptible cells. Subsequent dox withdrawal generates cells with a transcriptionally silent integrated provirus, but with an active shRNA expression cassette. Because the shRNA targets viral sequences that are removed from the vector construct, there is no self-targeting, yet there is specific shutdown of HIV-1 replication.

UI MeSH Term Description Entries
D004318 Doxycycline A synthetic tetracycline derivative with similar antimicrobial activity. 2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, (4S-(4alpha,4aalpha,5alpha,5aalpha,6alpha,12aalpha))-,Alpha-6-Deoxyoxytetracycline,Atridox,BMY-28689,BU-3839T,Doryx,Doxycycline Calcium,Doxycycline Calcium Salt (1:2),Doxycycline Hemiethanolate,Doxycycline Hyclate,Doxycycline Monohydrate,Doxycycline Monohydrochloride, 6-epimer,Doxycycline Monohydrochloride, Dihydrate,Doxycycline Phosphate (1:1),Doxycycline-Chinoin,Hydramycin,Oracea,Periostat,Vibra-Tabs,Vibramycin,Vibramycin Novum,Vibravenos,Alpha 6 Deoxyoxytetracycline,BMY 28689,BMY28689,BU 3839T,BU3839T,Doxycycline Chinoin,Doxycycline Monohydrochloride, 6 epimer,Vibra Tabs
D005822 Genetic Vectors DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition. Cloning Vectors,Shuttle Vectors,Vectors, Genetic,Cloning Vector,Genetic Vector,Shuttle Vector,Vector, Cloning,Vector, Genetic,Vector, Shuttle,Vectors, Cloning,Vectors, Shuttle
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013601 T-Lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D014779 Virus Replication The process of intracellular viral multiplication, consisting of the synthesis of PROTEINS; NUCLEIC ACIDS; and sometimes LIPIDS, and their assembly into a new infectious particle. Viral Replication,Replication, Viral,Replication, Virus,Replications, Viral,Replications, Virus,Viral Replications,Virus Replications
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015658 HIV Infections Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS). HTLV-III Infections,HTLV-III-LAV Infections,T-Lymphotropic Virus Type III Infections, Human,HIV Coinfection,Coinfection, HIV,Coinfections, HIV,HIV Coinfections,HIV Infection,HTLV III Infections,HTLV III LAV Infections,HTLV-III Infection,HTLV-III-LAV Infection,Infection, HIV,Infection, HTLV-III,Infection, HTLV-III-LAV,Infections, HIV,Infections, HTLV-III,Infections, HTLV-III-LAV,T Lymphotropic Virus Type III Infections, Human
D015693 Gene Products, nef Products of the retroviral NEF GENE. They play a role as accessory proteins that influence the rate of viral infectivity and the destruction of the host immune system. nef gene products were originally found as factors that trans-suppress viral replication and function as negative regulators of transcription. nef stands for negative factor. nef Gene Products,nef Protein,3'-orf Protein,Gene Product, nef,3' orf Protein,nef Gene Product
D015754 Genes, nef DNA sequences that form the coding region for a protein that down-regulates the expression of human immunodeficiency virus (HIV). nef is short for negative factor. HIV-3'-orf Genes,nef Genes,Gene, HIV-3'-orf,Gene, nef,Genes, HIV-3'-orf,HIV 3' orf Genes,HIV-3'-orf Gene,nef Gene

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