Achieving HIV-1 Control through RNA-Directed Gene Regulation

Klemm, Vera; Mitchell, Jye; Cortez‐Jugo, Christina; Cavalieri, Francesca; Symonds, Geoff; Caruso, Frank; Kelleher, Anthony D.; Ahlenstiel, Chantelle

doi:10.3390/genes7120119

Cited by 12 publications

(11 citation statements)

References 140 publications

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“…Retroviruses are named after their ability to transcribe RNA into DNA using their unique reverse transcriptase (RT), consequently allowing integration of retroviral DNA into the host genome. The integrated provirus can then establish a latent infection for the life of the host and is a major barrier to virus cure strategies, particularly for HIV-1 ( 117 ). Similar to viral RdRps, zinc has also been identified as an inhibitor of retrovirus RTs ( 118 , 119 ).…”

Section: Current Status Of Knowledgementioning

confidence: 99%

The Role of Zinc in Antiviral Immunity

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Ahlenstiel

et al. 2019

Advances in Nutrition

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Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation as a preventative and therapeutic treatment for viral infections.

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Section: Current Status Of Knowledgementioning

confidence: 99%

The Role of Zinc in Antiviral Immunity

Read

Obeid

Ahlenstiel

et al. 2019

Advances in Nutrition

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619

602

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“…This variability could have contributed to confounding results in our studies. Although there are promising clinical trials using RNAi to treat diseases, such as HIV [ 53 ], RNAi directed towards a single gene target is unlikely to have desired therapeutic effects, especially in brain injury due to the heterogeneous TBI patient population and complex injury profiles [ 54 ]. Despite specific targeting, gene delivery by siRNA vectors is highly complex and there are issues in overcoming critical thresholds of protein knockdown and in effective transduction of targeted cell types; these limitations hinder effective gene silencing in brain disorders [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of AAV-mediated knockdown of nNOS and GPx-1 gene expression in rat hippocampus after traumatic brain injury

et al. 2017

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Virally mediated RNA interference (RNAi) to knock down injury-induced genes could improve functional outcome after traumatic brain injury (TBI); however, little is known about the consequences of gene knockdown on downstream cell signaling pathways and how RNAi influences neurodegeneration and behavior. Here, we assessed the effects of adeno-associated virus (AAV) siRNA vectors that target two genes with opposing roles in TBI pathogenesis: the allegedly detrimental neuronal nitric oxide synthase (nNOS) and the potentially protective glutathione peroxidase 1 (GPx-1). In rat hippocampal progenitor cells, three siRNAs that target different regions of each gene (nNOS, GPx-1) effectively knocked down gene expression. However, in vivo, in our rat model of fluid percussion brain injury, the consequences of AAV-siRNA were variable. One nNOS siRNA vector significantly reduced the number of degenerating hippocampal neurons and showed a tendency to improve working memory. GPx-1 siRNA treatment did not alter TBI-induced neurodegeneration or working memory deficits. Nevertheless, microarray analysis of laser captured, virus-infected neurons showed that knockdown of nNOS or GPx-1 was specific and had broad effects on downstream genes. Since nNOS knockdown only modestly ameliorated TBI-induced working memory deficits, despite widespread genomic changes, manipulating expression levels of single genes may not be sufficient to alter functional outcome after TBI.

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“…An alternative to the CRISPR/Cas9 strategy is the silencing approach, which aims to reduce the production rate of HIV viral particles per integrated HIV DNA copy [68]. Lentiviral gene delivery enables RNA-based gene silencing, including the previously characterized small interfering RNA (siRNA) called PromA [30,132]. PromA is a short RNA sequence specific for the two NF-κB binding sites in the HIV LTR U3 region.…”

Section: Gene Therapy Strategies Against Hivmentioning

confidence: 99%

Gene Therapy Approaches to Functional Cure and Protection of Hematopoietic Potential in HIV Infection

Tsukamoto

2019

Pharmaceutics

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Although current antiretroviral drug therapy can suppress the replication of human immunodeficiency virus (HIV), a lifelong prescription is necessary to avoid viral rebound. The problem of persistent and ineradicable viral reservoirs in HIV-infected people continues to be a global threat. In addition, some HIV-infected patients do not experience sufficient T-cell immune restoration despite being aviremic during treatment. This is likely due to altered hematopoietic potential. To achieve the global eradication of HIV disease, a cure is needed. To this end, tremendous efforts have been made in the field of anti-HIV gene therapy. This review will discuss the concepts of HIV cure and relative viral attenuation and provide an overview of various gene therapy approaches aimed at a complete or functional HIV cure and protection of hematopoietic functions.

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Achieving HIV-1 Control through RNA-Directed Gene Regulation

Cited by 12 publications

References 140 publications

The Role of Zinc in Antiviral Immunity

The Role of Zinc in Antiviral Immunity

Effects of AAV-mediated knockdown of nNOS and GPx-1 gene expression in rat hippocampus after traumatic brain injury

Gene Therapy Approaches to Functional Cure and Protection of Hematopoietic Potential in HIV Infection

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