HIV-1 uses inositol hexakisphosphate (IP6) to build a metastable capsid capable of delivering its genome into the host nucleus. 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-cell lines. Restoring IP6 enrichment with a single mutation rescues the ability of HIV-1 to infect cells without being detected. Using a combination of capsid mutants and CRISPR-derived knockout cell lines for RNA and DNA sensors, we show that immune sensing is dependent upon the cGAS-STING axis and independent of capsid detection. Sensing requires the synthesis of viral DNA and is prevented by reverse transcriptase inhibitors or reverse transcriptase active-site mutation. These results demonstrate that IP6 is required to build capsids that can successfully transit the cell and avoid host innate immune sensing.
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