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Therapeutic interfering particle

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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[1][1] and are predicted to be resistance proof[2]. 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)[1]. The theoretical concept and formal definition of a therapeutic interfering particle were first proposed for HIV[2] based upon mathematical models of the mechanism of action[3] but the first successful demonstration of a therapeutic interfering particle was for SARS-CoV-2[1].

Definition & 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[1]. 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[4], and therapeutically reduce viral load[5]. 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[6]. TIPs have been engineered for HIV[5][4] and SARS-CoV-2, and do not induce innate immune responses such as interferon[1].

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[2]. 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[2].
  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.[2][3][5][7][8]

As a result of these mechanistic criteria, TIPs have been referred to as “piggyback”[1] or alternatively as “virus hijackers”.[2][3]

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[9] 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[10][11][12][13]. 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[14], and the DIP terminology was formalized in 1970 by Huang and Baltimore[15]. 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[9], the TIP concept (i.e., R0>1 mechanism of action) was first proposed in 2011[2], in theoretical models for a single-administration resistance-proof HIV intervention built off models of the mechanism of action proposed in the early 2000s[3].

In 2016 the US government launched a major funding initiative (DARPA INTERCEPT,[4],[5] ) to discover and engineer antiviral TIPs for diverse viruses, based on prior investments from the US National Institutes of Health,[6]. This program led to renewed interest in the concept of interfering particles as therapies with the development of technologies to isolate DIPs for influenza[16][17][18] and engineer TIPs for HIV and Zika virus[4]. The first successful experimental demonstration of the TIP concept was reported in 2019[5] for HIV, and the discovery of a TIP for SARS-CoV-2 was reported in 2021[1]. In 2020, the US government funded first-in-human clinical trials of TIPs, [7], [8].



References

  1. ^ a b c d e f g Chaturvedi, Sonali; Vasen, Gustavo; Pablo, Michael; Chen, Xinyue; Beutler, Nathan; Kumar, Arjun; Tanner, Elizabeth; Illouz, Sylvia; Rahgoshay, Donna; Burnett, John; Holguin, Leo (2021-12-09). "Identification of a therapeutic interfering particle—A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance". Cell. 184 (25): 6022–6036.e18. doi:10.1016/j.cell.2021.11.004. ISSN 0092-8674. PMC 8577993. PMID 34838159.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d e f Metzger, Vincent T.; Lloyd-Smith, James O.; Weinberger, Leor S. (2011-03-17). "Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies". PLoS Computational Biology. 7 (3): e1002015. doi:10.1371/journal.pcbi.1002015. ISSN 1553-734X. PMC 3060167. PMID 21483468.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b c d Weinberger, Leor S.; Schaffer, David V.; Arkin, Adam P. (2003-09). "Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection". Journal of Virology. 77 (18): 10028–10036. doi:10.1128/jvi.77.18.10028-10036.2003. ISSN 0022-538X. PMC 224590. PMID 12941913. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  4. ^ a b c Notton, Timothy; Glazier, Joshua J.; Saykally, Victoria R.; Thompson, Cassandra E.; Weinberger, Leor S. (2021-01-19). "RanDeL-Seq: a High-Throughput Method to Map Viral cis- and trans-Acting Elements". mBio. 12 (1): e01724–20. doi:10.1128/mBio.01724-20. ISSN 2150-7511. PMC 7845639. PMID 33468683.
  5. ^ a b c d Tanner, Elizabeth J.; Jung, Seung-Yong; Glazier, Joshua; Thompson, Cassandra; Zhou, Yuqi; Martin, Benjamin; Son, Hye-In; Riley, James L.; Weinberger, Leor S. (2019-10-30). "Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral": 820456. doi:10.1101/820456. {{cite journal}}: Cite journal requires |journal= (help)
  6. ^ Rouzine, Igor M.; Weinberger, Leor S. (2013-02). "Design requirements for interfering particles to maintain coadaptive stability with HIV-1". Journal of Virology. 87 (4): 2081–2093. doi:10.1128/JVI.02741-12. ISSN 1098-5514. PMC 3571494. PMID 23221552. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Tanner, Elizabeth J.; Kirkegaard, Karla A.; Weinberger, Leor S. (2016-05). "Exploiting Genetic Interference for Antiviral Therapy". PLoS genetics. 12 (5): e1005986. doi:10.1371/journal.pgen.1005986. ISSN 1553-7404. PMC 4858160. PMID 27149616. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  8. ^ Notton, Timothy; Sardanyés, Josep; Weinberger, Ariel D.; Weinberger, Leor S. (2014-08). "The case for transmissible antivirals to control population-wide infectious disease". Trends in Biotechnology. 32 (8): 400–405. doi:10.1016/j.tibtech.2014.06.006. ISSN 1879-3096. PMID 25017994. {{cite journal}}: Check date values in: |date= (help)
  9. ^ a b Dimmock, Nigel J.; Easton, Andrew J. (2014-5). "Defective Interfering Influenza Virus RNAs: Time To Reevaluate Their Clinical Potential as Broad-Spectrum Antivirals?". Journal of Virology. 88 (10): 5217–5227. doi:10.1128/JVI.03193-13. ISSN 0022-538X. PMC 4019098. PMID 24574404. {{cite journal}}: Check date values in: |date= (help)
  10. ^ von MAGNUS, P. (1951). "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. doi:10.1111/j.1699-0463.1951.tb03693.x. ISSN 0365-5555. PMID 14856732.
  11. ^ Von Magnus, P. (1951). "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. doi:10.1111/j.1699-0463.1951.tb00114.x. ISSN 0365-5555. PMID 14902470.
  12. ^ Von Magnus, P. (1954). "Incomplete forms of influenza virus". Advances in Virus Research. 2: 59–79. doi:10.1016/s0065-3527(08)60529-1. ISSN 0065-3527. PMID 13228257.
  13. ^ Von Magnus, P. (1952). "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. ISSN 0365-5555. PMID 14933064.
  14. ^ Hackett, A. J. (1964-09). "A POSSIBLE MORPHOLOGIC BASIS FOR THE AUTOINTERFERENCE PHENOMENON IN VESICULAR STOMATITIS VIRUS". Virology. 24: 51–59. doi:10.1016/0042-6822(64)90147-3. ISSN 0042-6822. PMID 14208902. {{cite journal}}: Check date values in: |date= (help)
  15. ^ Huang, A. S.; Baltimore, D. (1970-04-25). "Defective viral particles and viral disease processes". Nature. 226 (5243): 325–327. doi:10.1038/226325a0. ISSN 0028-0836. PMID 5439728.
  16. ^ Rand, Ulfert; Kupke, Sascha Young; Shkarlet, Hanna; Hein, Marc Dominique; Hirsch, Tatjana; Marichal-Gallardo, Pavel; Cicin-Sain, Luka; Reichl, Udo; Bruder, Dunja (2021-07-11). "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. doi:10.3390/cells10071756. ISSN 2073-4409. PMC 8303422. PMID 34359926.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ Pelz, Lars; Rüdiger, Daniel; Dogra, Tanya; Alnaji, Fadi G.; Genzel, Yvonne; Brooke, Christopher B.; Kupke, Sascha Y.; Reichl, Udo (2021-11-23). "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. doi:10.1128/JVI.01174-21. ISSN 1098-5514. PMC 8610589. PMID 34550771.
  18. ^ Tapia, Felipe; Laske, Tanja; Wasik, Milena A.; Rammhold, Markus; Genzel, Yvonne; Reichl, Udo (2019). "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: 275. doi:10.3389/fbioe.2019.00275. ISSN 2296-4185. PMC 6813217. PMID 31681751.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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