Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates
Abstract
Antiviral therapies with reduced frequencies of administration and high barriers to resistance remain a major goal. For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R0] > 1 (termed “therapeutic interfering particles” or “TIPs”), 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 >3log10 following a single intravenous injection. Animal lifespan was significantly extended, TIPs conditionally replicated and were continually detected for >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. These data provide proof of concept for a potential new class of single-administration antiviral therapies. Editor’s summary During replication, RNA viruses frequently generate defective particles that parasitize and interfere with the replication and packaging of intact virus. Such defective particles may also stimulate host immune responses. Pitchai et al. developed a continuous culture method in which deletions were cloned into HIV to generate therapeutic interfering particles (TIPs). First, they showed that transduction-competent viral-like particles were produced conditionally in trans with intact HIV and reduced HIV…
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