Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1.

Mon, 04/30/2018 - 10:23am -- dana
TitleInnate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1.
Publication TypeJournal Article
Year of Publication2017
AuthorsAroh C, Wang Z, Dobbs N, Luo M, Chen Z, Gao J, Yan N
JournalJ Immunol
Volume199
Issue11
Pagination3840-3848
Date Published2017 12 01
ISSN1550-6606
KeywordsAdenosine Monophosphate, Antigens, Viral, Cells, Cultured, Cyclic GMP, Endocytosis, HIV Infections, HIV-1, Humans, Hydrogen-Ion Concentration, Immunity, Innate, Immunotherapy, Interferon Type I, Leukocytes, Mononuclear, Lymphocyte Activation, Membrane Proteins, Monocytes, Nanoparticles, Signal Transduction, Virus Activation, Virus Replication
Abstract

HIV-1 evades immune detection by the cGAS-STING cytosolic DNA-sensing pathway during acute infection. STING is a critical mediator of type I IFN production, and STING agonists such as cGMP-AMP (cGAMP) and other cyclic dinucleotides elicit potent immune and antitumor response. In this article, we show that administration of cGAMP, delivered by an ultra-pH-sensitive nanoparticle (NP; PC7A), in human PBMCs induces potent and long-acting antiretroviral response against several laboratory-adapted and clinical HIV-1 isolates. cGAMP-PC7A NP requires endocytosis for intracellular delivery and immune signaling activation. cGAMP-PC7A NP-induced protection is mediated through type I IFN signaling and requires monocytes in PBMCs. cGAMP-PC7A NPs also inhibit HIV-1 replication in HIV patient PBMCs after ex vivo reactivation. Because pattern recognition receptor agonists continue to show more clinical benefits than the traditional IFN therapy, our data present important evidence for potentially developing cGAMP or other STING agonists as a new class of immune-stimulating long-acting antiretroviral agents.

DOI10.4049/jimmunol.1700972
Alternate JournalJ. Immunol.
PubMed ID29084836
PubMed Central IDPMC5916791
Grant ListR01 AI098569 / AI / NIAID NIH HHS / United States
R01 EB013149 / EB / NIBIB NIH HHS / United States
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