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The primary source of this activation is reverse transcription of the viral RNA genome into cDNA, which occurs in the cytoplasm. However, the degree of cytosolic DNA sensor activation during HIV-1 infection is significantly lower compared to that induced by DNA-containing viruses or even by the related HIV-2. This can be attributed to the successful evasion of innate immune recognition pathways by HIV-1, particularly through the disruption of cGAS-STING signaling pathway activation. In this review, we summarize the available information regarding the mechanisms employed by HIV-1 to conceal viral cDNA from cytosolic DNA sensors. Deciphering these mechanisms may reveal potential vulnerabilities that could be targeted to develop novel antiviral approaches.<\/jats:p>","DOI":"10.3390\/ijms262311635","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HIV-1 and Its Strategy for Hiding Viral cDNA from STING-Mediated Innate Immunity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5982-3990","authenticated-orcid":false,"given":"Anna","family":"Mashkovskaia","sequence":"first","affiliation":[{"name":"Chemistry Department, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6809-4670","authenticated-orcid":false,"given":"Yulia","family":"Agapkina","sequence":"additional","affiliation":[{"name":"Chemistry Department, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2262-117X","authenticated-orcid":false,"given":"Tatiana","family":"Oretskaya","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Gottikh","sequence":"additional","affiliation":[{"name":"Chemistry Department, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0590-5880","authenticated-orcid":false,"given":"Andrey","family":"Anisenko","sequence":"additional","affiliation":[{"name":"Chemistry Department, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway","volume":"339","author":"Sun","year":"2013","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1126\/science.1229963","article-title":"Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA","volume":"339","author":"Wu","year":"2013","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.celrep.2014.01.003","article-title":"The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop","volume":"6","author":"Zhang","year":"2014","journal-title":"Cell Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature07317","article-title":"STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling","volume":"455","author":"Ishikawa","year":"2008","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/s41586-019-1000-2","article-title":"Structural basis of STING binding with and phosphorylation by TBK1","volume":"567","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"ra20","DOI":"10.1126\/scisignal.2002521","article-title":"STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway","volume":"5","author":"Tanaka","year":"2012","journal-title":"Sci. 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