Broad Spectrum Anti-Viral Compound and Innate Immunity

[Mishma]

Some time ago I started a thread that explained our innate immune response, how it differed from our adaptive immune responses (think antibodies and cell mediated immunity) and how HIV circumvents one of our first lines of defense against pathogens and aberrant host cells. The new paper, on top of the references, describes a new compound that has profound effects against all dsRNA viruses tested-and some nasty ones at that and includes HEPC. Although not tested against HIV which is a ssRNA, this generalized approach should be applicable to it and other single stranded RNA viruses as well.

I've included an article from GIZMAG for a general overview as well as the research article it references. Also include are some relevant abstracts/links from PubMed on the general principals involved and background reading.



http://hsnewsbeat.uw.edu/sites/default/files/sites/default/files/documents/J.%20Virol.-2015.pdf

JVI Accepted Manuscript Posted Online 16 December 2015
J. Virol. doi:10.1128/JVI.02202-15
Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Targeting innate immunity for antiviral therapy through small molecule agonists of the
RLR pathway

 Sowmya Pattabhi, Courtney R. Wilkins, 3, Ran Dong2, Megan L. Knoll2, 3, Jeffrey
6 Posakony4, Shari Kaiser4, Chad E. Mire5, Myra L. Wang4, Renee C. Ireton2, 3, Thomas
7 W. Geisbert5, Kristin M. Bedard4, Shawn P. Iadonato3, 4, Yueh-Ming Loo2, 3#,
 Michael Gale Jr.1, 2, 3#.

 Departments of Global Health1 and Immunology2, and the Center for Innate Immunity
 and Immune Disease3, University of Washington, Seattle, Washington, USA;
 KINETA Inc., Seattle, Washington, USA4; University of Texas Medical Branch at
 Galveston, Galveston National Laboratory, Galveston, Texas, USA5

Running Head: RIG-I agonists as broad-spectrum antivirals.
 #Address correspondence to Michael Gale Jr., mgale@uw.edu and Yueh-Ming Loo,
 looy@uw.edu

  Abstract
 The cellular response to virus infection is initiated when pathogen recognition
 receptors (PRR) engage viral pathogen associated molecular patterns (PAMPs). This
 process results in induction of downstream signaling pathways that activate the
 transcription factor IRF3. IRF3 plays a critical role in antiviral immunity to drive the
 expression of innate immune response genes, including those encoding antiviral
 factors, type 1 interferon, and immune modulatory cytokines that act in concert to
 restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation
 and induce innate immune gene expression could serve as antivirals to induce tissue-
 wide innate immunity for effective control of virus infection. We identified small molecule
 compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes.
 We tested a lead compound and derivatives for the ability to suppress infection by a
 broad range of RNA viruses. Compound administration significantly decreased the viral
 RNA load in cultured cells that were infected with the family Flaviviridae, including West
 Nile virus, dengue virus and hepatitis C virus as well as viruses of the families
 Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa
 virus) and Paramyxoviridae (respiratory syncytial virus, Nipah virus) to suppress
 infectious virus production. Knockdown studies mapped this response to the RIG-I-like
 receptor pathway. This work identifies a novel class of host-directed immune
 modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infection by RNA viruses of distinct genera.


http://www.nature.com/icb/journal/v85/n6/full/7100100a.html

Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response

Alex J V Thompson1,2 and Stephen A Locarnini1

1Department of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
2Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia
Correspondence: Dr AJV Thompson, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn St.North Melbourne, Victoria 3051, Australia. E-mail: alexander.thompson@svhm.org.au

Received 9 June 2007; Accepted 14 June 2007; Published online 31 July 2007.


Abstract
The antiviral innate immune response follows the detection of viral components by host pattern recognition receptors (PRRs). Two families of PRRs have emerged as key sensors of viral infection: Toll-like receptors (TLRs) and retinoic acid inducible gene-I like RNA helicases (RLHs). TLRs patrol the extracellular and endosomal compartments; signalling results in a type-1 interferon response and/or the production of pro-inflammatory cytokines. In contrast, RLHs survey the cytoplasm for the presence of viral double-stranded RNA. In the face of such host defence, viruses have developed strategies to evade TLR/RLH signalling. Such host–virus interactions provide the opportunity for manipulation of PRR signalling as a novel therapeutic approach.



http://www.gizmag.com/compound-immune-response-rna-viruses/41026/?utm_source=Gizmag+Subscribers&utm_campaign=9af679f9e0-UA-2235360-4&utm_medium=email&utm_term=0_65b67362bd-9af679f9e0-91874541

Though important advances have been made in treating RNA virus infections such as hepatitis C and influenza, a broad spectrum antiviral drug that throws a blanket over all of them, including more deadly variants like Ebola, has remained out of reach. Scientists are now reporting the discovery of a drug-like molecule that could be used to combat all RNA viruses, by triggering an innate immune response that suppresses and controls the infections.

As a virus spreads through the body, it takes over individual cellular machinery and uses it to make copies of itself, infecting other cells in the process. While the body can fight off some viruses on its own, others are able to mutate to elude these natural defence mechanisms and go on replicating. Drugs have been developed to treat specific viruses, such as hepatitis C, but they are expensive and some hold concerns that their ongoing use may give rise to drug resistance.

So a team led by scientists from the University of Washington set out to better equip the body's immune system to fight off viral RNA. It has developed a compound that targets a molecule contained in the body's cells called RIG-1. This molecule is a pathogen recognition receptor, which means that it detects the presence of viral RNA and sets off an innate immune response inside the cell...........

http://www.ncbi.nlm.nih.gov/pubmed/21084468

J Virol. 2011 Feb;85(3):1224-36. doi: 10.1128/JVI.01635-10. Epub 2010 Nov 17.
RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I.
Solis M1, Nakhaei P, Jalalirad M, Lacoste J, Douville R, Arguello M, Zhao T, Laughrea M, Wainberg MA, Hiscott J.
Author information
Abstract
The rapid induction of type I interferon (IFN) is essential for establishing innate antiviral responses. During infection, cytoplasmic viral RNA is sensed by two DExD/H box RNA helicases, RIG-I and MDA5, ultimately driving IFN production. Here, we demonstrate that purified genomic RNA from HIV-1 induces a RIG-I-dependent type I IFN response. Both the dimeric and monomeric forms of HIV-1 were sensed by RIG-I, but not MDA5, with monomeric RNA, usually found in defective HIV-1 particles, acting as a better inducer of IFN than dimeric RNA. However, despite the presence of HIV-1 RNA in the de novo infection of monocyte-derived macrophages, HIV-1 replication did not lead to a substantial induction of IFN signaling. We demonstrate the existence of an evasion mechanism based on the inhibition of the RIG-I sensor through the action of the HIV-1 protease (PR). Indeed, the ectopic expression of PR resulted in the inhibition of IFN regulatory factor 3 (IRF-3) phosphorylation and decreased expression of IFN and interferon-stimulated genes. A downregulation of cytoplasmic RIG-I levels occurred in cells undergoing a single-cycle infection with wild-type provirus BH10 but not in cells transfected with a protease-deficient provirus, BH10-PR(-). Cellular fractionation and confocal microscopy studies revealed that RIG-I translocated from the cytosol to an insoluble fraction during the de novo HIV-1 infection of monocyte-derived macrophages, in the presence of PR. The loss of cytoplasmic RIG-I was prevented by the lysosomal inhibitor E64, suggesting that PR targets RIG-I to the lysosomes. This study reveals a novel PR-dependent mechanism employed by HIV-1 to counteract the early IFN response to viral RNA in infected cells.