Cyclic GMP-AMP Synthase is an Innate Immune Sensor of HIV and Other Retroviruses

By Daxing Gao, Jiaxi Wu, Youtong Wu, Fenghe Du, Chukwuemika Aroh, Nan Yan, Lijun Sun, Zhijian J. Chen. Science, 2013

993 citations recorded by the source corpus.

HIV Detection Is a (c)GAS Despite it being one of the most highly studied viruses, there are still many unknowns when it comes to HIV—including how it triggers the innate immune response. Gao et al. (p. 903, published 8 August) now demonstrate that the DNA sensor cyclic GMP-AMP synthase (cGAS) detects HIV infection. Reverse-transcribed HIV DNA triggers cGAS and downstream activation of antiviral immunity. Detection of HIV, as well as the retroviruses simian immunodeficiency virus and murine leukemia virus, was abrogated in mouse and human cells deficient in cGAS—suggesting that cGAS may be a critical activator of innate immunity in response to retroviral infection. Cell culture experiments suggest that detection of retroviral DNA activates cellular defense systems. Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

Subfields: Immunology, Virology

View Paper: https://www.semanticscholar.org/paper/15e6907acde5570197e9080c904ae978cfa6bde9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Zhijian J. Chen
2. Tuo Li
3. G. Barber
4. Xiang Chen
5. Y. Chiu
6. Xin Cai
7. Xiao-Dong Li
8. Daxing Gao

In Virology

1. G. Barber

Citations in the corpus

• The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, methodology): “Similarly, 2030-cGAMP binding induced a large conformational change of wild-type human STING (Figure 2B) (Gao et al., 2013c; Zhang et al., 2013).”
• Immune Responses to Viral Gene Therapy Vectors (2020, background): “This is likely because of sensing of viral DNA genomes (which result from reverse transcription) through a cytoplasmic mechanism that involves the cGAS-stimulator of IFN genes (STING) pathway.(123,124) cGAS is a cytosolic sensor of DNA.”
• STING: infection, inflammation and cancer (2015, positive): “Many DNA viruses have been reported to trigger STING-dependent activity, including adenovirus, vaccinia virus and papilloma virus 2,28-31 .The importance of the cGAS-STING axis has also been demonstrated for retrovirus infection including HIV [32] [33] [34] [35] .”
• Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases (2015, background): “Initial evidence that cGAS is responsible for activating the type-I IFN pathway in Trex1 cells was provided by findings that retroviruses such as HIV-1 robustly induced IFNs and ISGs in Trex1deficient cells and that such induction was abolished by TALENmediated knockout of cGas (39).”