Long-term inhibition of HIV-1 replication with RNA interference against cellular cofactors. Antiviral Res

ArticleinAntiviral research 89(1):43-53 · January 2011with10 Reads
Impact Factor: 3.94 · DOI: 10.1016/j.antiviral.2010.11.005 · Source: PubMed

In this study we tested whether HIV-1 replication could be inhibited by stable RNAi-mediated knockdown of cellular co-factors. Cell lines capable of expressing shRNAs against 30 candidate co-factors implicated at different steps of the viral replication cycle were generated and analyzed for effects on cell viability and inhibition of HIV-1 replication. For half of these candidate co-factors we obtained knockdown cell lines that are less susceptible to virus replication. For three co-factors (ALIX, ATG16 and TRBP) the cell lines were resistant to HIV-1 replication for up to 2 months. With these cells we could test the hypothesis that HIV-1 is not able to escape from RNAi-mediated suppression of cellular co-factors, which was indeed not detected.

    • "Other cellular factors like autophagy related 16-like (Atg-16), autophagy related 5-like (Atg-5), Heat Shock 60 kDa protein (Chaperonin), TSG101, and ALIX which supports various stages of the HIV life cycle, were also shown to block HIV replication. A study to determine the effects of 30 known cellular factors on HIV replication demonstrated that cell lines expressing siRNA against ALIX, Atg-16 and TRBP genes were resistant to HIV replication for up to two months [53]. A subsequent study demonstrated that knockdown of various autophagy factors including Beclin-1, WIPI-1, PIK3R4, Atg-4, Atg-5, and Atg-16, inhibited HIV replication by blocking the production of viral particles. "
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    • "replication experiments838485868788. However, HIV-1 causes a chronic infection and infected patients require long-term treatment, which cannot easily be accomplished for synthetic siRNAs, in part due to inefficient delivery of nucleic acids into cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs) with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described.
    Full-text · Article · Jul 2015 · Viruses
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    • "As HIV-1 is capable of modulating the immune system through TRBP-TAR-mediated inhibition of PKR-or SOCS1-dysregulation of immune activation, silencing these genes results in an antiviral response [124]. RNAi silencing of TRBP can also inhibit HIV-1 replication [75, 125, 126], but this could potentially disrupt the RNAi pathway because of the role of TRBP in Dicer processing and RISC assembly [127]. In general, cellular targets must be considered with caution because these targets affect cell growth and function, and because they may be important for cell signaling not observed in vitro. "
    [Show abstract] [Hide abstract] ABSTRACT: HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery.
    Full-text · Article · May 2015 · Genome Medicine
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