Document Detail


Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells.
MedLine Citation:
PMID:  23316755     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Immune response modifiers are being studied as therapeutic agents for viral infections and cancer. These molecules include agonists for the Toll-like receptors (TLR), a family of innate immune receptors. TLR7 and 8, located in cellular endosomes, bind single-stranded RNA characteristic of viral genomes, and trigger intracellular signaling pathways that induce inflammatory cytokines and antiviral innate immune factors. We studied the anti-HIV-1 effects of gardiquimod, a specific TLR7 agonist when used at concentrations below 10 μM, in macrophages and activated peripheral blood mononuclear cells (PBMCs). Gardiquimod, added prior to or within 2 days after infection with X4, R5, or dual-tropic (R5/X4) strains of HIV-1, significantly reduced infection in these cells. Cocultures of activated PBMCs added to gardiquimod-treated and HIV-1-exposed macrophages demonstrated minimal HIV-1 replication for up to 10 days, suggesting that gardiquimod inhibited activated PBMCs viral amplification from HIV-1-exposed macrophages. Gardiquimod treatment of both activated PBMCs and macrophages induced interferon-alpha (IFN-α) transcription within hours of addition, and sustained IFN-α protein secretion for several days. Treatment of cells with a peptide inhibitor to the MyD88 adaptor protein blocked the induction of IFN-α by gardiquimod, and partially reversed the anti-HIV effects in activated PBMCs. Blocking the IFN-α receptor with a neutralizing antibody also reduced the anti-HIV effect of gardiquimod. Gardiquimod inhibited HIV-1 reverse transcriptase, an early step in the life cycle of HIV-1. These findings suggest that gardiquimod, functioning as both an immune system modifier and a reverse transcriptase inhibitor, could be developed as a novel therapeutic agent to block systemic and mucosal transmission of HIV-1.
Authors:
Maarten Buitendijk; Susan K Eszterhas; Alexandra L Howell
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Publication Detail:
Type:  Journal Article     Date:  2013-02-05
Journal Detail:
Title:  AIDS research and human retroviruses     Volume:  29     ISSN:  1931-8405     ISO Abbreviation:  AIDS Res. Hum. Retroviruses     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-13     Completed Date:  2013-08-30     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8709376     Medline TA:  AIDS Res Hum Retroviruses     Country:  United States    
Other Details:
Languages:  eng     Pagination:  907-18     Citation Subset:  IM; X    
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MeSH Terms
Descriptor/Qualifier:
Aminoquinolines / therapeutic use*
Anti-HIV Agents / therapeutic use*
Cell Line
DNA, Viral / genetics
HIV Infections / drug therapy*
HIV-1 / drug effects*,  physiology
Humans
Imidazoles / therapeutic use*
Interferon-alpha / biosynthesis
Leukocytes, Mononuclear / drug effects,  virology
Macrophages / drug effects,  virology*
Real-Time Polymerase Chain Reaction
T-Lymphocytes / drug effects,  virology*
Toll-Like Receptor 7 / agonists*
Virus Replication / drug effects
Chemical
Reg. No./Substance:
0/Aminoquinolines; 0/Anti-HIV Agents; 0/DNA, Viral; 0/Imidazoles; 0/Interferon-alpha; 0/Toll-Like Receptor 7; 0/gardiquimod
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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