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Here, we show that viruses that are unable to package IP6 lack capsid protection and are detected by innate immunity, resulting in the activation of an antiviral state that inhibits infection. Disrupting IP6 enrichment results in defective capsids that trigger cytokine and chemokine responses during infection of both primary macrophages and T\u2010cell lines. Restoring IP6 enrichment with a single mutation rescues the ability of HIV\u20101 to infect cells without being detected. Using a combination of capsid mutants and CRISPR\u2010derived knockout cell lines for RNA and DNA sensors, we show that immune sensing is dependent upon the cGAS\u2013STING axis and independent of capsid detection. Sensing requires the synthesis of viral DNA and is prevented by reverse transcriptase inhibitors or reverse transcriptase active\u2010site mutation. These results demonstrate that IP6 is required to build capsids that can successfully transit the cell and avoid host innate immune sensing.<\/jats:p>","DOI":"10.15252\/embr.202256275","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T04:23:46Z","timestamp":1679891026000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["IP6\u2010stabilised HIV capsids evade cGAS\/STING\u2010mediated host immune sensing"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5215-0014","authenticated-orcid":false,"given":"Guido","family":"Papa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3672-5498","authenticated-orcid":false,"given":"Anna","family":"Albecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2713-5215","authenticated-orcid":false,"given":"Donna","family":"Mallery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Vaysburd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Renner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-0334","authenticated-orcid":false,"given":"Leo C","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"BFEMBR202256275_CR1","doi-asserted-by":"crossref","first-page":"5486","DOI":"10.1073\/pnas.1920631117","volume":"117","author":"RC Burdick","year":"2020","unstructured":"Burdick RC, Li C, Munshi MH, Rawson JMO, Nagashima K, Hu WS, Pathak VK (2020) HIV\u20101 uncoats in the nucleus near sites of integration. 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