Therapeutic interfering particle

Short description: Drug class

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. Similar to Defective Interfering Particles (DIPs), 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.[1][2] But, in contrast to DIPs, TIPs are engineered to have an in vivo basic reproductive ratio (R0) that is greater than 1 (R0>1).[3] The term "TIP" was first introduced in 2011[4] based on models of its mechanism-of-action from 2003.[3] Given their unique R0>1 mechanism of action, TIPs exhibit high barriers to the evolution of antiviral resistance[5] and are predicted to be resistance proof.[4] 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 HIV or COVID-19).[6][4][3][7][5] Synthetic DIPs that rely on stimulating innate antiviral immune responses (i.e., interferon) were proposed for influenza in 2008[8] and shown to protect mice to differing extents [9][10][11] but are technically distinct from TIPs due to their alternate molecular mechanism of action which has not been predicted to have a similarly high barrier to resistance.[12] Subsequent work tested the pre-clinical efficacy of TIPs against HIV,[6] a synthetic DIP for SARS-CoV-2 (in vitro),[7] and a TIP for SARS-CoV-2 (in vivo).[5][13]

## 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.[5] 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,[14] and therapeutically reduce viral load.[6] 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.[15] TIPs have been engineered for HIV[6][14] and SARS-CoV-2,[7] and do not induce innate immune responses such as interferon[5]

Three mechanistic criteria define a TIP:

1. Conditional replication: Due to a lack of genes required for replication, TIPs cannot self-replicate. However, when wild-type virus is present in the same cell (i.e., there is a superinfection of the cell), it provides the missing intracellular replication resources, allowing TIPs to conditionally replicate.[4] In molecular genetics terms, the wild-type virus is said to provide complementation in trans.
2. Interference via competitive inhibition: TIPs reduce wild-type virus replication specifically by competing for intracellular viral replication resources (e.g., packaging proteins like the capsid). This mechanism of action reduces wild-type virus burst size and provides TIPs with a high genetic barrier to the evolution of viral resistance.[4]
3. Mobilization with R0>1: when a TIP is conditionally activated by the wild-type "helper" virus in a super-infected cell, it will generate virus-like particles (VLPs). These TIP VLPs mobilize from the cell, are phenotypically identical to the virus being targeted, and can transduce new target cells. The central requirement for a therapeutic interfering particle is that it mobilizes with a basic reproductive ratio (R0) that is greater than 1 (R0>1). That is, for every TIP-producing cell, more than one new TIP-transduced cell must be generated. This third characteristic differentiates TIPs from naturally occurring DIPs.[4][3][6][16][12]

As a result of these mechanistic criteria, TIPs have been referred to as "piggyback"[17] or alternatively as "virus hijackers".[18][19]

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., R0>1), as innate immune mechanisms inhibit efficient mobilization of TIPs.[3] As such, several VLP-based therapy proposals for influenza and other viruses[20] 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.[21][22][23][2] 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,[24] and the DIP terminology was formalized in 1970 by Huang and Baltimore.[25] DIPs have been reported for many classes of DNA and RNA viruses in clinical and laboratory settings.

Whereas DIPs had been proposed as potential therapeutics that would act via stimulation of the immune system[20] – a concept[8][26] tested in influenza with mixed results[9][10] – the TIP R0>1 mechanism of action was first proposed in 2003[3] with the term "TIP" and the unique benefits of the R0>1 mechanism shown in 2011.[4]

In 2016 the US government launched a major funding initiative (DARPA INTERCEPT,[26][27][28] ) to discover and engineer antiviral TIPs for diverse viruses, based on prior investments from the US National Institutes of Health.[29] This program led to renewed interest in the concept of interfering particles as therapies with the development of technologies to isolate DIPs for influenza[30][31][32] and engineer TIPs for HIV and Zika virus.[14] The first successful experimental demonstration of the TIP concept was reported in 2019[6] for HIV, and the discovery of a TIP for SARS-CoV-2 was reported in 2020[7] and results on the effect on hamsters in 2021.[33] In 2020, the US government funded first-in-human clinical trials of TIPs.[34][35]

## References

1. ↑ Huang, Alice S.; Baltimore, David (April 1970). "Defective Viral Particles and Viral Disease Processes" (in en). Nature 226 (5243): 325–327. doi:10.1038/226325a0. ISSN 1476-4687. PMID 5439728. Bibcode: 1970Natur.226..325H. https://www.nature.com/articles/226325a0.
2. ↑ 2.0 2.1 "Propagation of the PR8 strain of influenza A virus in chick embryos. IV. Studies on the factors involved in the formation of incomplete virus upon serial passage of undiluted virus". Acta Pathologica et Microbiologica Scandinavica 30 (3–4): 311–335. 1952. doi:10.1111/j.1699-0463.1952.tb00185.x. PMID 14933064.
3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection". Journal of Virology 77 (18): 10028–10036. September 2003. doi:10.1128/jvi.77.18.10028-10036.2003. PMID 12941913.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Autonomous targeting of infectious superspreaders using engineered transmissible therapies". PLOS Computational Biology 7 (3). March 2011. doi:10.1371/journal.pcbi.1002015. PMID 21483468. Bibcode: 2011PLSCB...7E2015M.
5. ↑ 5.0 5.1 5.2 5.3 5.4 "Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance" (in English). Cell 184 (25): 6022–6036.e18. December 2021. doi:10.1016/j.cell.2021.11.004. PMID 34838159.
6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Tanner EJ, Jung SY, Glazier J, Thompson C, Zhou Y, Martin B, Son HI, Riley JL, Weinberger LS (January 2019). "Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral". bioRxiv 10.1101/820456.
7. ↑ 7.0 7.1 7.2 7.3 "A synthetic defective interfering SARS-CoV-2". PeerJ 9. 2020-11-23. doi:10.7717/peerj.11686. PMID 34249513.
8. ↑ 8.0 8.1 "Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral". Journal of Virology 82 (17): 8570–8578. September 2008. doi:10.1128/JVI.00743-08. PMID 18579602.
9. ↑ 9.0 9.1 "Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established". PLOS ONE 7 (12). 2012-12-12. doi:10.1371/journal.pone.0049394. PMID 23251341. Bibcode: 2012PLoSO...749394D.
10. ↑ 10.0 10.1 "Comparison of the protection of ferrets against pandemic 2009 influenza A virus (H1N1) by 244 DI influenza virus and oseltamivir". Antiviral Research 96 (3): 376–385. December 2012. doi:10.1016/j.antiviral.2012.09.017. PMID 23041142.
11. ↑ "Defective interfering influenza virus confers only short-lived protection against influenza virus disease: evidence for a role for adaptive immunity in DI virus-mediated protection in vivo". Vaccine 29 (38): 6584–6591. September 2011. doi:10.1016/j.vaccine.2011.06.114. PMID 21762748.
12. ↑ 12.0 12.1 "The case for transmissible antivirals to control population-wide infectious disease". Trends in Biotechnology 32 (8): 400–405. August 2014. doi:10.1016/j.tibtech.2014.06.006. PMID 25017994.
13. ↑ Chaturvedi, Sonali; Beutler, Nathan; Vasen, Gustavo; Pablo, Michael; Chen, Xinyue; Calia, Giuliana; Buie, Lauren; Rodick, Robert et al. (27 September 2022). "A single-administration therapeutic interfering particle reduces SARS-CoV-2 viral shedding and pathogenesis in hamsters" (in en). Proceedings of the National Academy of Sciences 119 (39). doi:10.1073/pnas.2204624119. ISSN 0027-8424. PMID 36074824. Bibcode: 2022PNAS..11904624C.
14. ↑ 14.0 14.1 14.2 "RanDeL-Seq: a High-Throughput Method to Map Viral cis\- and trans-Acting Elements". mBio 12 (1): e01724–20. January 2021. doi:10.1128/mBio.01724-20. PMID 33468683.
15. ↑ "Design requirements for interfering particles to maintain coadaptive stability with HIV-1". Journal of Virology 87 (4): 2081–2093. February 2013. doi:10.1128/JVI.02741-12. PMID 23221552.
16. ↑ "Exploiting Genetic Interference for Antiviral Therapy". PLOS Genetics 12 (5). May 2016. doi:10.1371/journal.pgen.1005986. PMID 27149616.
17. ↑ "Piggyback Virus Could Curb HIV Pandemic". Wired. https://www.wired.com/2011/03/virus-therapy-hiv/.
18. ↑ "Can we create vaccines that mutate and spread?". TED Talks. TED Conferences, LLC. March 2020. https://www.ted.com/talks/leor_weinberger_can_we_create_vaccines_that_mutate_and_spread.
19. ↑ "The virus hijacker". The Times. 19 August 2004. https://www.thetimes.com/uk/science/article/the-virus-hijacker-gj8wctld3hc.
20. ↑ 20.0 20.1 "Defective interfering influenza virus RNAs: time to reevaluate their clinical potential as broad-spectrum antivirals?". Journal of Virology 88 (10): 5217–5227. May 2014. doi:10.1128/JVI.03193-13. PMID 24574404.
21. ↑ "Propagation of the PR8 strain of influenza A virus in chick embryos. II. The formation of incomplete virus following inoculation of large doses of seed virus". Acta Pathologica et Microbiologica Scandinavica 28 (3): 278–293. 1951. doi:10.1111/j.1699-0463.1951.tb03693.x. PMID 14856732.
22. ↑ "Propagation of the PR8 strain of influenza A virus in chick embryos. III. Properties of the incomplete virus produced in serial passages of undiluted virus". Acta Pathologica et Microbiologica Scandinavica 29 (2): 157–181. 1951. doi:10.1111/j.1699-0463.1951.tb00114.x. PMID 14902470.
23. ↑ "Incomplete forms of influenza virus". Advances in Virus Research 2: 59–79. 1954. doi:10.1016/s0065-3527(08)60529-1. PMID 13228257.
24. ↑ "A possible morphologic basis for the autointerference phenomenon in vesicular stomatitis virus". Virology 24: 51–59. September 1964. doi:10.1016/0042-6822(64)90147-3. PMID 14208902.
25. ↑ "Defective viral particles and viral disease processes". Nature 226 (5243): 325–327. April 1970. doi:10.1038/226325a0. PMID 5439728. Bibcode: 1970Natur.226..325H.
26. ↑ 26.0 26.1 "INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT)". Defense Advanced Research Projects Agency. U.S. Department of Defense. https://www.darpa.mil/program/intercept.
27. ↑ "DARPA INTERCEPT Program for Biodefense Countermeasures". 11 April 2016. https://globalbiodefense.com/2016/04/11/darpa-bto-intercept-therapeutic-platform/.
28. ↑ "To Fight a Virus, Get a Virus: Military Bets on Mutant Pathogen". Bloomberg. 14 July 2016. https://www.bloomberg.com/news/articles/2016-07-14/mutant-hiv-viruses-fight-new-infections-in-two-brothers-labs.
29. ↑ "Weinberger receives 2013 NIH Director's Pioneer Award". UCSF School of Pharmacy. University of California - San Francisco. 6 January 2014. https://pharmacy.ucsf.edu/news/2014/01/weinberger-receives-2013-nih-directors-pioneer-award.
30. ↑ "Antiviral Activity of Influenza A Virus Defective Interfering Particles against SARS-CoV-2 Replication In Vitro through Stimulation of Innate Immunity". Cells 10 (7): 1756. July 2021. doi:10.3390/cells10071756. PMID 34359926.
31. ↑ "Semi-continuous Propagation of Influenza A Virus and Its Defective Interfering Particles: Analyzing the Dynamic Competition To Select Candidates for Antiviral Therapy". Journal of Virology 95 (24): e0117421. November 2021. doi:10.1128/JVI.01174-21. PMID 34550771.
32. ↑ "Production of Defective Interfering Particles of Influenza A Virus in Parallel Continuous Cultures at Two Residence Times-Insights From qPCR Measurements and Viral Dynamics Modeling". Frontiers in Bioengineering and Biotechnology 7. 2019. doi:10.3389/fbioe.2019.00275. PMID 31681751.
33. ↑ "Defective interfering viruses and their potential as antiviral agents". Reviews in Medical Virology 20 (1): 51–62. January 2010. doi:10.1002/rmv.641. PMID 20041441.
34. ↑ "Joint Warfighter Medical". Congressionally Directed Medical Research Programs (CDMRP). https://cdmrp.army.mil/jwmrp/awards/20mmrdawards_hssacto.aspx. "FY20 Military Medical Research and Development Award - Human Subjects/Sample Acquisition with Clinical Trial Option"
35. ↑ "DARPA Seeks First-in-Human Therapeutic Interfering Particles Targeting Respiratory Viruses". Global Biodefense. 27 May 2019. https://globalbiodefense.com/2019/05/27/darpa-seeks-first-in-human-therapeutic-interfering-particle-tip-targeting-respiratory-viruses/.

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