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GARDIQUIMOD: A TOLL LIKE RECEPTOR-7 AGONIST THAT INHIBITS HIV-1 INFECTION OF HUMAN MACROPHAGES AND ACTIVATED T CELLS.
MedLine Citation:
PMID:  23316755     Owner:  NLM     Status:  Publisher    
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 anti-viral 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 (PBMC). Gardiquimod added prior to or within two days after infection with X4, R5 or dual-tropic (R5/X4) strains of HIV-1, significantly reduced infection in these cells. Co-cultures of activated PBMC added to gardiquimod-treated and HIV-1-exposed macrophages demonstrated minimal HIV-1 replication for up to 10 days, suggesting that gardiquimod inhibited activated PBMC viral amplification from HIV-1-exposed macrophages. Gardiquimod treatment of both activated PBMC 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 PBMC. 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 Howell
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  AIDS research and human retroviruses     Volume:  -     ISSN:  1931-8405     ISO Abbreviation:  AIDS Res. Hum. Retroviruses     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709376     Medline TA:  AIDS Res Hum Retroviruses     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Geisel School of Medicine at Dartmouth, Physiology, Lebanon, New Hampshire, United States; Maarten.Buitendijk@Dartmouth.EDU.
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