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For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R\n                    <jats:sub>0<\/jats:sub>\n                    ] &gt; 1 (termed \u201ctherapeutic interfering particles\u201d or \u201cTIPs\u201d), could parasitize wild-type virus to constitute single-administration, escape-resistant antiviral therapies. We report the engineering of a TIP that, in rhesus macaques, reduces viremia of a highly pathogenic model of HIV by &gt;3log\n                    <jats:sub>10<\/jats:sub>\n                    following a single intravenous injection. Animal lifespan was significantly extended, TIPs conditionally replicated and were continually detected for &gt;6 months, and sequencing data showed no evidence of viral escape. A single TIP injection also suppressed virus replication in humanized mice and cells from persons living with HIV. 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