What Kind Of Animal Models Are Used In Viral Vectors
Comp Med. 2017 Jun; 67(3): 215–221.
Published online 2017 Jun.
Viral Vector Biosafety in Laboratory Animal Research
Dalis E Collins
iBaylor College of Medicine, Houston, Texas;
Jon D Reuter
2University of Colorado, Boulder, Colorado; and
Howard G Rush
threeAcademy of Michigan, Ann Arbor, Michigan
Jason S Villano
3University of Michigan, Ann Arbor, Michigan
Received 2016 Oct 27; Revised 2016 December 16; Accustomed 2016 December 28.
Abstruse
Viral vector research presents unique occupational wellness and safety challenges to institutions due to the rapid development of both in vivo and in vitro factor-editing technologies. Risks to human and animal health brand it incumbent on institutions to appropriately evaluate viral vector usage in research on the footing of bachelor data and governmental regulations and guidelines. Here we review the factors related to risk cess regarding viral vector usage in animals and the relevant regulatory documents associated with this research, and we highlight the nearly commonly used viral vectors in inquiry today. This review is particularly focused on the groundwork, use in research and associated health and environmental risks related to adenoviral, adeno-associated viral, lentiviral, and herpesviral vectors.
Abbreviations: AAV, adeno-associated viral vector; ABSL, creature biosafety level; BMBL, Biosafety in Microbiologic and Biomedical Laboratories; RG, risk group
The utilise of viral vectors in research is increasing, both in beast research and human cistron therapy trials. As of June 2012, a total of 1843 gene therapy trials accept been undertaken in 31 countries, most of which have used transduction (Effigy i) as a cistron-delivery tool.22 A PubMed search with keywords viral vector showed a consistent increment in publications in this arena over the last 15 y (Figure ii). Even so, research in viral vector biosafety in the laboratory animal setting has not risen in parallel, which is reflected in the relatively few publications during the aforementioned period.
Common viral vector terminology.
PubMed searches for the terms 'viral vector' compared with 'viral vector biosafety' for the indicated time intervals returned results indicating a steadily increasing and disproportionately higher number of publications focused on viral vector enquiry as compared with publications focused specifically on viral vector biosafety. Searches performed on 24 September 2016.
In assessing risk regarding viral vector use in animal research, one must consider the hazards inherent to the viral vector itself, the animal model, the inserted gene construct, and the proposed research manipulations. A great deal is known about the original virus from which the vectors are genetically engineered, including replicative power, oncogenic potential, environmental stability, tissue and cellular tropism (amphotropic compared with ecotropic; Effigy 1), and pathogenic characteristics—all of which helps to guide adventure cess.thirteen,16-eighteen,xx,31 In addition, data regarding shedding duration, excretion routes, biodistribution, and other components vital to appropriate run a risk assessment of vectors is available from basic research studies and human gene therapy trials.44,47 Even so, informative data from these clinical trials does non always interpret to brute models, thus leaving a huge gap in the knowledge base needed to make accurate gamble assessments. Genetic manipulations to increase safety such as pseudotyping (Figure one) and the creation of conditionally replicating viral vectors must likewise be considered. The use of humanized mice has been proposed as a concluding pace in preclinical viral vector risk assessment, but this condition does not address the inherent risks involved in creature research.three Hazards implicit in working with animals such as bites and scratches can only be mitigated so much by engineering science controls and personal protective equipment. In add-on, the expansive utilize of sometimes uncharacterized transgenic animals makes it impossible to adequately conceptualize all potential risk scenarios. Oftentimes the greatest unknown is the event of the transgene itself inside the specific creature model. Institutions take more than control over administrative practices meant to mitigate risks specific to the experimental protocol, including balls of proper training and proficiency and occupational health assessment of research personnel.
The hazards associated with viral vectors go far incumbent on institutions to acquit gamble assessment to make informed decisions regarding policies and guidelines. Even with the large number of prior viral vector gene therapy clinical trials performed with no significant sick effects in participants, sometimes life-threatening effects have been observed in a modest number of participants and thus highlight potential repercussions from inappropriate handling and usage.43,49 This cess is challenging for brute care and apply programs, given the level of expertise in virology, human and animal physiology, and other disciplines needed to appropriately evaluate literature. In this review, nosotros nowadays electric current regulations, literature, and industry practices for some of the near widely used viral vector agents (adenoviruses, lentiviruses, herpesviruses, and adeno-associated viruses [AAV]). We evaluate general characteristics, known hazards, and risk reduction practices in light of recent advances in molecular biological science and viral engineering, in the hope of aiding institutions in their individual evaluations.
Current Regulations
Institutions receiving federal funding are field of study to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, impl mented by the Recombinant DNA Advisory Commission.2 These guidelines stipulate protocol review past the Institutional Biosafety Committee and outline required containment and rubber procedures. Near viral vectors are classified by the NIH equally belonging to either Adventure Group (RG) i (not associated with disease in healthy man adults) or RG2 (associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available). Biosafety level (BL) containment requirements are stipulated for each risk group (BL1 or BL2).39 In improver to RG1 agents, viral vectors containing less than 2/three of a eukaryotic viral genome may be handled nether BL1 conditions. However, near viral vectors used in creature enquiry are either RG2 agents or do not encounter this size requirement and therefore require BL2 containment and procedures during preparation, manipulation, and injection. These precautions include restricted access, an appropriate laboratory set-up and signage, staff grooming, sharps prophylactic, decontamination of waste prior to disposal, and personal protective equipment to prevent skin and mucous membrane exposure.vii
For animal experiments involving about viral vectors used in research, the NIH Guidelines recommend BL2N (BL2–Animate being; Effigy i) containment practices. Because of the operational challenges of continuous BL2N containment, further clarification was released for lentiviral vectors, recommending BL2N containment housing for iii to 7 d.52 As discussed earlier, viral–host interactions cannot always be predicted when viral vectors are used in transgenic animals, and accordingly, the NIH Guidelines stress that "serious consideration should exist given to increasing the containment conditions."39 Biosafety in Microbiologic and Biomedical Laboratories (BMBL, 5th edition) can likewise be used as a guidance document for working with poorly characterized viral vectors.12 Many institutions do not distinguish betwixt beast biosafety level (ABSL) 1 through 4 (equally described in the BMBL) and BLN1 through 4, choosing instead to follow specifications provided in the BMBL, which also covers work with other infectious agents. As such, nosotros reference ABSL containment levels throughout this document for clarity.
Adenoviral vectors
Replication-competent and -scarce adenoviruses are classified as RG2 agents. Adenoviruses are nonenveloped double-stranded DNA viruses (Baltimore classification grouping 1) that have wide species and cellular tropism (amphotropic). Without alterations, adenoviruses practise not integrate efficiently into the genome and therefore expression is by and large transient. In adenoviral vectors, most of which are derived from type 5 adenoviruses,28 the key replication elements are deleted. New 'gutless' systems consist of only the adenoviral packaging organization and contain no adenoviral genomic material, thus increasing biosafety in terms of immunogenicity and cytotoxicity.13 Conditionally replicating adenoviruses, which replicate selectively in tumor cells, are available.thirteen
Given the ubiquity of adenoviruses in the surround, most people have previously been exposed to adenoviruses although immunity to the virus is generally strain-specific. Adenoviruses most commonly crusade mild respiratory illness or conjunctivitis in good for you adults just tin crusade more serious disease, specially in immunocompromised persons. These viruses are transmitted by straight contact, ingestion, droplets, and percutaneous exposure.12 Even in experimental animal models, establishing vertical transmission or germline transduction of adenoviruses is very hard.24 Long-term shedding can occur through respiratory secretions and feces from asymptomatic carriers. However, humans who received an adenoviral vector through intravenous administration had minimal shedding in biologic fluids after 48 h, due to sequestration by the liver.28 Hamsters and cotton rats (Sigmodon hispidus) are the just ii mutual laboratory species in which unmanipulated human adenoviruses tin can replicate.thirteen
Although natural disease is generally mild, adenoviruses are notoriously immunogenic. Adenoviral vectors are preferred for vaccination vectors, given their fix uptake by antigen presenting cells, particularly Kupffer cells.10 Several episodes of inflammatory responses to adenovirus vectors in clinical trials have been documented, including 1 death subsequently direct injection of an adenoviral vector into the hepatic avenue.33 Some first-generation adenoviral vectors, which retain a great proportion of the genome, have initiated dose-dependent apoptosis of various target cells in vitro and in multiple mouse models in vivo, indicating a potential for straight cytotoxicity.51,56 The widespread distribution and tropism of adenoviruses supports the potential for intracellular recombination or complementation (Figure 1) of the vector with previously acquired wild-type adenovirus in either packaging cell lines or in vivo, thus making the adenoviral vector replication-competent. This risk can be reduced considerably by using prison cell lines with decreased or no homology between vector and helper sequences.21 Some other risk-reduction strategy is regular quality-control checks of viral vector stocks for low levels of contagion with replication-competent virus. No standards for this kind of monitoring are available currently, and threshold levels are determined arbitrarily by investigators.44
Adeno-associated Viral Vectors
Adeno-associated viral vectors (AAV), the most mutual parvoviral vectors, are more often than not classified under RG1. Exceptions include synthetic or recombinant AAV constructs produced in the presence of a helper virus and those that contain a potentially harmful transgene (Appendix B1 of the NIH Guidelines).39 Parvoviruses are nonenveloped single-stranded Deoxyribonucleic acid viruses (Baltimore nomenclature II). Although parvoviruses by and large take a narrow host range, they are of involvement in viral vector research because of their ability to infect both dividing and nondividing cells.15 However, they do not integrate efficiently into the host genome, and as such their expression is more often than not transient. AAV vectors get their name from their requirement for a helper plasmid or virus for propagation. Constructive helper viruses include adenovirus, canker simplex virus, vaccinia virus, and human papilloma virus. AAV cellular tropism is strain-dependent.xviii AAV tin can infect humans and other primate species just are not known to cause illness. Approximately 80% of humans are seropositive to AAV strains.v
AAV vectors take a favorable safety tape in clinical trials and preclinical animal studies.eighteen,35 In one clinical trial, recombinant AAV vectors administered beneath the retina resulted in no detectable systemic vector dissemination and no indication of any mounted immune response to the vector.22 Most risks associated with AAV viral vectors are theoretical in nature. For example, although wild-blazon AAV inserts at a known locus in the human being genome with no ill effects, recombinant AAV vectors can integrate randomly or at other points with potential prooncogenic results.26,40 In some animal models, the integration of recombinant AAV has been associated with an increased incidence of tumor germination, but this association has not been noted to occur in humans.45 Although ineffective in replication as an isolated amanuensis, AAV have the potential for replication competence in the presence of a helper plasmid or virus, and stock solutions should be tested for the presence of other agents. However, autonomous replication has occurred under stressful genotoxic conditions (UV light exposure, hydroxyurea incubation) in some cell lines1,55 and differentiating keratinocytes.34 Finally, as hydrophilic nonenveloped viruses, parvoviruses are known for their environmental stability.
Herpesviral Vectors
Herpesviruses are double-stranded enveloped DNA viruses (Baltimore nomenclature ane) with relatively large genomes. Herpesviruses are ubiquitous in the beast kingdom but species-specific in their host tropism and are classified into 1 of 3 subfamilies (α, β, and γ). Canker simplex virus types 1 and 2 (HSV1 and HSV2) are αherpesviruses, which are epitheliotropic cytolytic viruses that can form lifelong infections by establishing latency in neural tissue with intermittent recrudescence in response to stress and other factors.29 Because they are human pathogens, herpesviral vectors are classified under RG2. In all HSV vectors, genes that encode for accompaniment or essential proteins have been manipulated, such that their products minimally to completely inhibit viral replication and lytic ability, respectively.29 Viral stocks are then produced by using cells lines that provide these protein products through complementation.
Compared with the other viruses described in this review, HSV vectors are used only rarely in clinical trials, just their neural tropism and ability to plant latency allowing a sustained transgene expression get in an attractive target for gene therapy for peripheral neuropathies.7,23 Genetic manipulation has led to the creation of 3 types of HSV vectors: amplicon, replication-defective, and replication-competent. Created in the late 1980s, amplicon vectors contain the origin of replication and packaging genes but lack lytic function. Amplicons crave transduction with a helper virus for competent infection and are used extensively in preclinical inquiry due to their ability to accept very large inserts (100 kb).48 Improvements were made to avert stock contagion with helper viruses by further deletion of packaging genes. Replication-lacking HSV vectors have come up a long way since their inception in the early on 1990s, with the deletion of essential replicative genes. One of the largest roadblocks to the utilize of replication-deficient HSV vectors is direct cytotoxicity, presumptively due to replication-independent mechanisms of cytoskeletal disruption.four,27 In 2015, the development of a 3rd-generation HSV vector capable of long-term cistron expression without cytotoxicity or interference with jail cell division represents one of the concluding breakthroughs needed to make HSV a widely useful gene-commitment applied science.36 Finally, replication-competent HSV vectors are in the advanced stage of evolution for oncolytic cancer therapy.
Although molecular alterations to the viral genome take dramatically reduced virus-associated risks, HSV remains a known human pathogen with inflammatory and immunomodulatory furnishings. Although the seroprevalence of both HSV1 and HSV2 is high in the United states (approximately 53% and 16%, respectively),6 few solid data that support in vivo recombination or complementation are bachelor. Master infection with HSV1 tin be mild or inapparent and unremarkably occurs in early on childhood. In active infections, lesions are generally express to the mucocutaneous junctions, genitalia (HSV2), or epidermis. Yet, fatal meningoencephalitis tin can occur, especially in immunocompromised persons.7,31 HSV are transmitted by direct contact and mucous membrane exposure with trunk excretions and respiratory droplets.2 Apparently asymptomatic carriers tin can shed sporadically. In rats infected with wild-type HSV, subsequent intracranial injection of HSV vectors did not lead to viral reactivation of the vector.54 However, multiple strains of HSV were isolated from the neuronal tissue of a single patient, thus perchance supporting intratypic recombination rather than successive infection.33 As an enveloped virus, HSV is inherently unstable in the environment. Although susceptible to many common disinfectants (bleach, Lysol [Reckitt Benckiser, Parsippany, NJ], Alcide [Ecolab, St Paul, MN]), HSV2 is more thermolabile than HSV1, and increased disinfectant concentrations or prolonged contact times may be required for inactivation, depending on the subtype.14
Lentiviral Vectors
Lentiviruses are a type of retrovirus (Baltimore classification Seven) and consist of a unmarried-stranded positive-sense RNA sequence that is transcribed into a DNA and integrated into the host genome, causing persistent infection. Lentiviruses have several unique characteristics that may brand them preferred over vectors derived from other genera of retroviruses, such every bit gammaretroviruses, including integration into nondividing cells and the ability to transduce stem cells more efficiently, such that lower infection doses can be used.38 Most lentiviral vector systems are based on altered HIV types 1 and two and contain deletions or alterations of some or all pathogenic (vpr, vpx, and nef) and replication-dependent (gag–pol and env) genetic elements, depending on which lentiviral vector generation is used.xvi Unmanipulated HIV1 and HIV2 are in RG3, merely manipulated lentiviruses used as viral vectors (that is, altered HIV1 and HIV2) are in RG 2.39
Wildtype HIV1 and HIV2 infect CD4+ T helper cells, causing an immunosuppressed land and eventual progression to AIDS, which is characterized by the evolution of opportunistic infections.xvi In comparing the two subtypes, HIV2 has a lower infectivity rate, longer asymptomatic period, and slower illness progression than HIV1. Although HIV1 infections are the virtually common in the Us, HIV2 is an important cause of disease in other regions. Coinfection with HIV1 and HIV2 is infrequent compared with the well-recognized intercladal and intracladal HIV1 coinfections.9 HIV transmission occurs through mucous membrane exposure, direct contact with actual fluids including sexual transmission, percutaneous exposure, and vertical transmission.xvi Antiviral therapy has been established to be effective in preventing HIV infection if used appropriately in the context of postexposure prophylaxis.
Lentiviral vectors are generally considered to be relatively safe, given their extensive genetic alterations in recent years through which components necessary for virus product have been separate across multiple plasmids, some of which are integrated into the viral vector, and others that are expressed just within the packaging system.xvi Each dissever of the lentiviral genome makes propagation outside of the cell line packaging system more difficult through mechanisms of complementation or recombination. Second-generation lentiviral vectors use 3 plasmids, third-generation vectors use 4 plasmids, and fourth-generation vectors use 5 plasmids.nineteen,25,46,l Other alterations to increase safety include the production of self-inactivating vectors (Figure ane) and improved packaging systems that use less HIV genomic fabric.xix,37
Clinical trials in which lentiviral vectors were used to treat adrenoleukodystrophy, a fatal demyelinating disease, yielded no adverse furnishings.22 However, the apply of lentiviral vectors in research is however associated with potential risks, and the long-term safety of these clinical interventions is still beingness evaluated. An initial in vitro study showed no propagation of replication-deficient lentiviral vectors in cell civilisation after 3 washes with PBS.1 Nonetheless a after written report found that cells incubated with lentiviral vectors can betrayal secondary target cells to infection despite repeated washings (that is, ii washes) and in the absenteeism jail cell-to-cell contact both in vitro and in vivo.41 Although these findings disharmonize, they might signal a potential route of transmission to nontarget tissues through spill-over shedding of viral particles into the cellular supernatant.41 Although lentiviral vectors are less associated with insertional mutagenesis (Figure 1) than other retroviruses, these vectors even so provide evidence regarding off-target effects. For example, one participant in a clinical trial to care for β-thalassemia by cells transduced by using self-inactivating lentivirus demonstrated the emergence of a partially ascendant cell clone of myeloid progenitor origin after injection with transduced hematopoietic stalk cells. This can either represent a stochastic event in the context of a low initial number of transduced cells or the precursor to a potentially malignant progression which is ever a concern for lentiviral integration events.11 Long-term follow-up of this patient is ongoing at this time.eleven Nevertheless, lentiviruses are not stable in the environment and are susceptible to almost disinfectants, making decontamination straightforward.
Word
In 2015, a survey to decide common containment housing and practices among institutions involved in viral vector apply in animal enquiry was conducted past using an online questionnaire (Inquiry Suite, Qualtrics, Provo, UT) sent through the CompMed listserve (AALAS, Memphis, TN). Responses were received from a total of 44 institutions, of which 41 (93%) were bookish institutions and nonprofit organizations. Table 1 presents data gathered from the participants, some of whom returned responses only to select questions of the survey. In summary, well-nigh institutions business firm animals that received lentiviral and adenoviral vectors under ABSL2 conditions for a few days after administration or for the duration of the experiment. However, institutions may cull to downgrade containment from ABSL2 to ABSL1 for creature housing, provided that ABLS2 practices are followed during vector administration or that specific genetic alterations have been made to the viral vector itself (such as pseudotyping or replication incompetence).
Tabular array one.
Summary of CompMed survey responses
| Lentiviral vectors | Adenoviral vectors | |
| ABSL1 | 0 (0%) | 1 (3%) |
| Animals receive washed, transduced cells | ||
| Testify of replication incompetence | ||
| ABSL1 with special procedures | 3 (7%) | 2 (6%) |
| Use of biosafety cabinet for vector preparation and administration to animals | ||
| All wastes are considered biohazardous | ||
| ABSL2 for i to 7 d after administration | 29 (66%) | 21 (60%) |
| Generally at to the lowest degree 72 h | ||
| ABSL2 for elapsing of experiment | ix (20%) | 10 (29%) |
| But for replication-competent vectors | ||
| Other measures | 3 (seven%) | 1 (3%) |
| Total | 44 (100%) | 35 (100%) |
When performing a risk assessment to determine containment levels, consider the host species and its immune status, relevant viral vector modifications, inoculation strategy (titer, route of delivery, and tissue), and gene insert. Intravenous administration of adenoviral, AAV, and lentiviral vectors into either immunocompetent and immunocompromised (NOD-SCID) mice does non increment the take chances of viral vector shedding when E1a/b-, E3-deleted type 5 adenoviruses, rAAV2/2, or 3rd-generation lentiviral vectors are used.44 Once delivered, the replication-deficient vectors limited proteins in target tissues just show no evidence of propagation. Withal, some information propose that intravenous delivery can atomic number 82 to leaking at the point of injection. Both lentiviral and adenoviral vectors tin be establish on tail swabs for equally long as 72 h subsequently injection, although this positivity was localized, and no vector was recovered from the bedding.44 To farther minimize the hazard of contamination of the environment, the injection site should exist wiped with a disinfectant, given that viral vectors are rapidly cleared (that is, within 24 h) from the blood.44 Vectors persist on caging or in bedding for much less time than practise wildtype virus.53 Furthermore, intracranial delivery methods are designed as closed injection systems that apply small volumes such that the potential of superficial contagion is minimal when properly performed.
Because of the potential for the presence of viral vectors in the environment later inoculation, sanitize caging and equipment between uses to preclude manual by fomites. When placed on untreated plastic, recombinant AAV and adenoviral vectors were recoverable by cell culture for three and 14 d respectively.44 In an evaluation of several disinfectants for in vitro efficacy against viral vectors (lentiviral, adenoviral, and AAV), only Virkon S (Dupont, Wilmington, DE) demonstrated robust surface disinfection and minimal aversion, making it preferable for use on surfaces that rodents contact.8 For many studies, sanitation through a muzzle wash system is appropriate because temperatures achieved past about industrial muzzle washers (74 °C for half dozen min) are sufficient to eliminate the gamble of adenoviral transmission.32,42 Like precautions likely volition exist sufficient for lentiviruses and herpesviruses likewise, given their relative instability in the environment.
For standard replication-deficient adenoviral, 3rd-generation herpesviral vectors, and third- and 4th-generation lentiviral vectors, nosotros recommend an initial 72-h menstruum of ABSL2 containment followed past reclassification to ABSL1 housing afterward a consummate cage change. Following the recommendations of the NIH Guidelines together with the demonstrated safety of AAV vectors, ABSL1 housing is sufficient provided that the encoded transgene is accounted safe and appropriate precautions are taken during vector preparation and administration.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482513/
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