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IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.


ABSTRACT: Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes -TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING-TBK1-IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages.

SUBMITTER: Jakobsen MR 

PROVIDER: S-EPMC3845190 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.

Jakobsen Martin R MR   Bak Rasmus O RO   Andersen Annika A   Berg Randi K RK   Jensen Søren B SB   Tengchuan Jin J   Laustsen Anders A   Hansen Kathrine K   Ostergaard Lars L   Fitzgerald Katherine A KA   Xiao T Sam TS   Mikkelsen Jacob G JG   Mogensen Trine H TH   Paludan Søren R SR  

Proceedings of the National Academy of Sciences of the United States of America 20131023 48


Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human ma  ...[more]

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