Innate Immunity

The innate immune response is our body’s first line of defense against infections by bacteria or viruses. During HIV infection, cells can recognize specific signals given by an invading virus and trigger a signaling cascade that alerts the rest of the body to the infection. Unfortunately, HIV has developed ways to evade and hide from our innate immune system, making it difficult to fight against the infection. To assist in this battle, researchers have been working hard to better understand how to activate our innate immune system in response to HIV. The following animations depict research based scenarios in which innate immune sensors are able to detect HIV and trigger an innate immune response.

cGAS-STING Pathway

Cyclic GMP-AMP synthase or cGAS plays an important role in detecting foreign double-stranded DNA in the cytoplasm. When cGAS detects and binds DNA, it produces a secondary messenger called, cGAMP, which then goes on to activate the adaptor protein STING. From there, a signaling cascade occurs leading to the activation of the transcription factor IRF3. This ultimately leads the release of interferon related proteins that then alert neighboring cells to activate their own interferon response, thereby creating a protective cellular environment that prevents the spread of HIV. In order to activate the cGAS-STING pathway, researchers have been developing methods to crack open the HIV-1 capsid while in the cytoplasm and before integration can occur. By using small molecules such as Lenacapavir, the HIV-1 DNA can become exposed to the cytoplasm thereby allowing cGAS to detect and bind the intruder.

MDA5 Activation

MDA5 is a cytosolic viral RNA sensor that can bind viral double-stranded RNA through its c-shaped helicase domain. Subsequent activation of MDA5 has been shown to lead to a signaling cascade that results in increased levels of pro-inflammatory cytokines. During the life cycle of HIV-1, unspliced RNA produced by the HIV-1 provirus is exported from the nucleus to the cytoplasm. This unspliced HIV-1 RNA has been shown to activate a type 1 interferon response, but for many years the innate immune receptor that detects unspliced HIV-1 RNA was unknown. Fortunately, new research suggests that MDA5 plays a key role in this detection and may contribute to the inflammation people living with HIV-1 experience.

Animation created by Rachel Torrez in collaboration with Dr. Jarrod Johnson’s lab at the University of Utah

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Animation created by Rachel Torrez in collaboration with Dr. Jeremy Luban’s lab at the University of Massachusetts Medical School

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    (9)          Varadi, M.; Anyango, S.; Deshpande, M.; Nair, S.; Natassia, C.; Yordanova, G.; Yuan, D.; Stroe, O.; Wood, G.; Laydon, A.; Žídek, A.; Green, T.; Tunyasuvunakool, K.; Petersen, S.; Jumper, J.; Clancy, E.; Green, R.; Vora, A.; Lutfi, M.; Figurnov, M.; Cowie, A.; Hobbs, N.; Kohli, P.; Kleywegt, G.; Birney, E.; Hassabis, D.; Velankar, S. AlphaFold Protein Structure Database: Massively Expanding the Structural Coverage of Protein-Sequence Space with High-Accuracy Models. Nucleic Acids Research 2022, 50 (D1), D439–D444. https://doi.org/10.1093/nar/gkab1061.

    (10)          Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Žídek, A.; Potapenko, A.; Bridgland, A.; Meyer, C.; Kohl, S. A. A.; Ballard, A. J.; Cowie, A.; Romera-Paredes, B.; Nikolov, S.; Jain, R.; Adler, J.; Back, T.; Petersen, S.; Reiman, D.; Clancy, E.; Zielinski, M.; Steinegger, M.; Pacholska, M.; Berghammer, T.; Bodenstein, S.; Silver, D.; Vinyals, O.; Senior, A. W.; Kavukcuoglu, K.; Kohli, P.; Hassabis, D. Highly Accurate Protein Structure Prediction with AlphaFold. Nature 2021, 596 (7873), 583–589. https://doi.org/10.1038/s41586-021-03819-2.