Therapeutic interfering particle
A therapeutic interfering particle is an antiviral preparation that reduces the replication rate and pathogenesis of a particular viral infectious disease. A therapeutic interfering particle is typically a biological agent (i.e., nucleic acid) engineered from portions of the viral genome being targeted. The agent competes with the pathogen within an infected cell for critical viral replication resources, reducing the viral replication rate and resulting in reduced pathogenesis. Given this mechanism of action, therapeutic interfering particles exhibit high barriers to the evolution of antiviral resistance. and are predicted to be resistance proof. Intervention with therapeutic interfering particles can  be prophylactic (to prevent or ameliorate the effects of a future infection), or a single-administration therapeutic (to fight a disease that has already occurred, such as COVID-19). The theoretical concept and formal definition of a therapeutic interfering particle were first proposed for influenza in 2008 and later for HIV based upon mathematical models of the mechanism of action. Therapeutic interfering particles were shown to protect mice to differing extents in 2009. The first therapeutic interfering particle for SARS-CoV-2 was tested in vitro in 2020 and in vivo in 2021. Mechanism of action. Therapeutic Interfering Particles, often referred to  as TIPs, are typically synthetic, engineered versions of naturally occurring defective interfering particles (DIPs), in which critical portions of the virus genome are deleted rendering the TIP unable to replicate on its own. Often a TIP has the vast majority of the virus genome deleted. However, TIPs are engineered to retain specific elements of the genome that allow them to efficiently compete with the wild-type virus for critical replication resources inside an infected cell. TIPs thereby deprive wild-type virus of replication material through competitive inhibition, and therapeutically reduce viral load. Competitive inhibition enables TIPs to conditionally replicate and  efficiently mobilize between cells, essentially "piggybacking" on wild-type virus, to act as single-administration antivirals with a high genetic barrier to the evolution of resistance. TIPs have been engineered for HIV and SARS-CoV-2, and do not induce innate immune responses such as interferon Three mechanistic criteria define a TIP: As a result of these mechanistic criteria, TIPs have been referred to as "piggyback" or alternatively as "virus hijackers". TIPs do not stimulate or function through the induction of innate cellular immune responses (such as interferon). In fact, stimulation of innate cellular antiviral mechanisms has been shown to contravene  criterion (#3) (i.e., R>1), as innate immune mechanisms inhibit efficient mobilization of TIPs. As such, several VLP-based therapy proposals for influenza and other viruses that do not satisfy these criteria are DIPs, but not TIPs. History. TIPs are built off the phenomenon of defective interfering particles (DIPs) discovered by Preben Von Magnus in the early 1950s, during his work on influenza viruses. DIPs are spontaneously arising virus mutants, first described by von Magnus as "incomplete" viruses, in which a critical portion of the viral genome has been lost. Direct evidence for DIPs was only found in the 1960s by  Hackett, who observed the presence of "stumpy" particles of vesicular stomatitis virus in electron micrographs, and the DIP terminology was formalized in 1970 by Huang and Baltimore. DIPs have been reported for many classes of DNA and RNA viruses in clinical and laboratory settings. While DIPs had long been proposed as potential therapeutic agents that would act via stimulation of the immune system., the TIP concept was proposed and tested in influenza with mixed results. The R>1 mechanism of action was first proposed in 2011, in theoretical models for a single-administration resistance-proof HIV intervention built off models of  the mechanism of action proposed in the early 2000s. In 2016 the US government launched a major funding initiative (DARPA INTERCEPT, ) to discover and engineer antiviral TIPs for diverse viruses, based on prior investments from the US National Institutes of Health. This program led to renewed interest in the concept of interfering particles as therapies with the development of technologies to isolate DIPs for influenza and engineer TIPs for HIV and Zika virus. Successful experimental demonstration of the TIP concept was reported in 2019 for HIV, and the discovery of a TIP for SARS-CoV-2 was reported in 2020 and  results on the effect on hamsters in 2021. In 2020, the US government funded first-in-human clinical trials of TIPs,