Virus-like particle

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Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural proteins, which can then self assemble into the virus-like structure. [1] [2] [3] [4] Combinations of structural capsid proteins from different viruses can be used to create recombinant VLPs. VLPs derived from the Hepatitis B virus (HBV) and composed of the small HBV derived surface antigen (HBsAg) were described in 1968 from patient sera. [5] VLPs have been produced from components of a wide variety of virus families including Parvoviridae (e.g. adeno-associated virus), Retroviridae (e.g. HIV), Flaviviridae (e.g. Hepatitis C virus), Paramyxoviridae (e.g. Nipah) and bacteriophages (e.g. Qβ, AP205). [1] VLPs can be produced in multiple cell culture systems including bacteria, mammalian cell lines, insect cell lines, yeast and plant cells. [6] [7]

Contents

VLPs can also refer to structures produced by some LTR retrotransposons (under Ortervirales) in nature. These are defective, immature virions, sometimes containing genetic material, that are generally non-infective due to the lack of a functional viral envelope. [8] [9] In addition, wasps produce polydnavirus vectors with pathogenic genes (but not core viral genes) or gene-less VLPs to help control their host. [10] [11]

Applications

This diagram shows how surrogate viruses expressing the SARS-CoV-2 spike protein can be used to measure the activity of neutralizing antibodies that target the spike protein and prevent the virus from entering host cells. 238054 web surrogate viruses.jpg
This diagram shows how surrogate viruses expressing the SARS-CoV-2 spike protein can be used to measure the activity of neutralizing antibodies that target the spike protein and prevent the virus from entering host cells.

Therapeutic and imaging agents

VLPs are a candidate delivery system for genes or other therapeutics. [12] These drug delivery agents have been shown to effectively target cancer cells in vitro. [13] It is hypothesized that VLPs may accumulate in tumor sites due to the enhanced permeability and retention effect, which could be useful for drug delivery or tumor imaging. [14]

Vaccines

VLPs are useful as vaccines. VLPs contain repetitive, high density displays of viral surface proteins that present conformational viral epitopes that can elicit strong T cell and B cell immune responses.; [15] the particles' small radius of roughly 20-200 nm allows for sufficient draining into lymph nodes. Since VLPs cannot replicate, they provide a safer alternative to attenuated viruses. VLPs were used to develop FDA-approved vaccines for Hepatitis B and human papillomavirus, which are commercially available.

There are currently a selection of vaccines against human papilloma virus (HPV) such as Cervarix by GlaxoSmithKline along with Gardasil and Gardasil-9, produced by Merck & Co. Gardasil consists of recombinant VLPs assembled from the L1 proteins of HPV types 6, 11, 16, and 18 expressed in yeast and is adjuvanted with aluminum hydroxyphosphate sulfate. Gardasil-9 consists of L1 epitopes of 31, 33, 45, 52 and 58 in addition to the listed L1 epitopes found in Gardasil. Cervarix consists of recombinant VLPs assembled from the L1 proteins of HPV types 16 and 18, expressed in insect cells, and is adjuvanted with 3-O-Desacyl-4-monophosphoryl lipid (MPL) A and aluminum hydroxide. [16]

The first VLP vaccine that addresses malaria, Mosquirix, (RTS,S) has been approved by regulators in the EU. It was expressed in yeast. RTS,S is a portion of the Plasmodium falciparum circumsporozoite protein fused to the Hepatitis B surface antigen (RTS), combined with Hepatitis B surface antigen (S), and adjuvanted with AS01 (consisting of (MPL)A and saponin).

Research suggests that VLP vaccines against influenza virus could provide stronger and longer-lasting protection against flu viruses than conventional vaccines. [17] Production can begin as soon as the virus strain is sequenced and can take as little as 12 weeks, compared to 9 months for traditional vaccines. In early clinical trials, VLP vaccines for influenza appeared to provide complete protection against both the Influenza A virus subtype H5N1 and the 1918 flu pandemic. [18] Novavax and Medicago Inc. have run clinical trials of their VLP flu vaccines. [19] [20]

VLPs have also been used to develop a pre-clinical vaccine candidate against chikungunya virus. [15]

Lipoparticle technology

The VLP lipoparticle was developed to aid the study of integral membrane proteins. [21] Lipoparticles are stable, highly purified, homogeneous VLPs that are engineered to contain high concentrations of a conformationally intact membrane protein of interest. Integral Membrane proteins are involved in diverse biological functions and are targeted by nearly 50% of existing therapeutic drugs. However, because of their hydrophobic domains, membrane proteins are difficult to manipulate outside of living cells. Lipoparticles can incorporate a wide variety of structurally intact membrane proteins, including G protein-coupled receptors (GPCR)s, ion channels and viral Envelopes. Lipoparticles provide a platform for numerous applications including antibody screening, production of immunogens and ligand binding assays. [22] [23]

Assembly

The understanding of self-assembly of VLPs was once based on viral assembly. This is rational as long as the VLP assembly takes place inside the host cell (in vivo), though the self-assembly event was found in vitro from the very beginning of the study about viral assembly. [24] Study also reveals that in vitro assembly of VLPs competes with aggregation [25] and certain mechanisms exist inside the cell to prevent the formation of aggregates while assembly is ongoing. [26]

Linking targeting groups to VLP surfaces

Attaching proteins, nucleic acids, or small molecules to the VLP surface, such as for targeting a specific cell type or for raising an immune response is useful. In some cases a protein of interest can be genetically fused to the viral coat protein. [27] However, this approach sometimes leads to impaired VLP assembly and has limited utility if the targeting agent is not protein-based. An alternative is to assemble the VLP and then use chemical crosslinkers, [28] reactive unnatural amino acids [29] or SpyTag/SpyCatcher reaction [30] [31] in order to covalently attach the molecule of interest. This method is effective at directing the immune response against the attached molecule, thereby inducing high levels of neutralizing antibody and even being able to break tolerance to self-proteins displayed on VLPs. [31]

Related Research Articles

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<i>Orthomyxoviridae</i> Family of RNA viruses including the influenza viruses

Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

Pseudoviridae is a family of viruses, which includes three genera.

Original antigenic sin

Original antigenic sin, also known as antigenic imprinting or the Hoskins effect, refers to the propensity of the body's immune system to preferentially utilize immunological memory based on a previous infection when a second slightly different version of that foreign pathogen is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to a form of original antigenic sin, termed repertoire freeze.

Duck hepatitis B virus, abbreviated DHBV, is part of the genus Avihepadnavirus of the Hepadnaviridae, and is the causal agent of duck hepatitis B.

Herpes simplex virus Species of virus

Herpes simplex virus1 and 2, also known by their taxonomical names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of new viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are common and contagious. They can be spread when an infected person begins shedding the virus.

Virosome

A virosome is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid membrane vesicle incorporating virus derived proteins to allow the virosomes to fuse with target cells. Viruses are infectious agents that can replicate in their host organism, however virosomes do not replicate. The properties that virosomes share with viruses are based on their structure; virosomes are essentially safely modified viral envelopes that contain the phospholipid membrane and surface glycoproteins. As a drug or vaccine delivery mechanism they are biologically compatible with many host organisms and are also biodegradable. The use of reconstituted virally derived proteins in the formation of the virosome allows for the utilization of what would otherwise be the immunogenic properties of a live-attenuated virus, but is instead a safely killed virus. A safely killed virus can serve as a promising vector because it won't cause infection and the viral structure allows the virosome to recognize specific components of its target cells.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

Viral entry

Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, there are several shared generalities concerning viral entry.

Virus Small non-cellular infectious agent that only replicates in cells

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E1 (HCV)

E1 is one of two subunits of the envelope glycoprotein found in the hepatitis C virus. The other subunit is E2. This protein is a type 1 transmembrane protein with a highly glycosylated N-terminal ectodomain and a C-terminal hydrophobic anchor. After being synthesized the E1 glycoproteins associates with the E2 glycoprotein as a noncovalent heterodimer.

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<i>Lagovirus</i> Genus of viruses

Lagovirus is a genus of viruses, in the family Caliciviridae. Lagomorphs serve as natural hosts. There are two species in this genus. Diseases associated with this genus include: necrotizing hepatitis leading to fatal hemorrhages.

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