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Retroviruses and Retrovirus (Including Lentivirus) Vectors

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Retroviruses and Retrovirus (Including Lentivirus) Vectors A General Introduction to and Guidance on Retroviruses and Retrovirus (including Lentivirus) Vectors Guidance 1. Classification/Nomenclature Retrovirus nomenclature can be confusing into two sub-families, Orthoretrovirinae and because a variety of terms are used to describe Spumaretrovirinae. The first sub-family contains various properties of the family. The six genera, Alpharetrovirus, Betaretrovirus, International Committee for Taxonomy of Gammaretrovirus, Deltaretrovirus, Epsilon- Viruses (ICTV) split the Retroviridae family retrovirus and Lentivirus while the second contains the single Spumavirus genus (Table 1). Table 1: Retroviridae Family Classification Subfamily Genus Typical Examples Orthoretrovirinae Alpharetrovirus Avian leukosis virus (ALV), Rous sarcoma virus (RSV) Avian myeloblastoma virus Moloney Murine leukaemia virus MMLV (defective - encodes v-myb oncogene) Moloney Murine sarcoma virus (encodes v-src oncogene) Betaretrovirus Mouse mammary tumor virus (MMTV), Jaasichte sheep retrovirus and Mason-Pfizer monkey virus (MPMV) Gammaretrovirus Murine leukemia virus (MLV), Feline leukemia virus (FELV) Deltaretrovirus Bovine leukemia virus, Human T-cell lymphotrophic virus -1 (HTLV-1) Human T-cell lymphotrophic virus -2 (HTLV-2) Epsilonretrovirus Walleye dermal sarcoma virus Lentivirus Human immunodeficiency virus 1 and 2 (HIV1, 2) Simian immunodeficiency virus (SIV) Feline immunodeficiency virus (FIV) Equine infectious anaemia virus (EIAV) Visna/maedi virus Spumaretrovirinae Spumavirus Simian foamy virus, Human foamy virus Prepared by: Safety Office Approved by: Biosafety Committee Issue date October 2019 Retrovirus/Vectors guidance v3 Page 1 of 14 Review date October 2022 2. Virus Morphology Classification based on these morphological details has now been largely superceded by Historically speaking retroviruses were information derived from sequence data. classified into groups based on their morphology in negatively-stained electron microscope 3. Virion Structure pictures. A-type virus possessed a non- enveloped immature intracellular particle As implied above by the morphological believed to result from endogenous retrovirus appearance of virions in the EM there are like genetic elements. B-type viruses were considerable differences between various types extra-cellular with prominent envelope spikes of retrovirus; what follows is a simplified and an electron dense, acentric core, typified by description of the particle. The standard MMTV. The C-type group included most nomenclature for retrovirus proteins along with mammalian and avian retroviruses and was their basic function is illustrated in Table 2. All similar to B-type viruses with a central core but of these proteins are essential for replication; with poorly visible envelope spikes. The D-type some retroviruses, particularly those in the delta, virus group appeared slightly larger, up to epsilon, lentivirus and spumavirus genera 120nm in size, with less prominent envelope encode additional essential and non-essential proteins e.g. Mason-Pfizer monkey virus (which is proteins. now classified as a Betaretrovirus). Table 2 Protein Function Matrix (MA) A matrix protein (gag gene product) which lines the envelope Capsid (CA) A capsid protein (gag gene product); protects the core and is the most abundant protein in the virus particle Nucleocapsid (NC) A capsid protein (gag gene product); protects the genome and forms the core of the particle Protease (PR) Required for gag protein cleavage during maturation Reverse transcriptase (RT) Reverse transcribes the RNA genome; also has RNAseH activity Integrase (IN) Encoded by the pol gene; needed for integration of the provirus Surface glycoprotein (SU) The outer envelope glycoprotein; binds to the viral receptor on the target cell surface Transmembrane protein (TM) The inner component of the mature envelope glycoprotein, mediates cell membrane fusion with virion Prepared by: Safety Office Approved by: Biosafety Committee Issue date October 2019 Retrovirus/Vectors guidance v3 Page 2 of 14 Review date October 2022 4. Virus tropism as polytropic have also been used to refer to viruses that are capable of infecting murine and The commonly used terms, ecotropic, xenotropic, non murine cells. amphotropic and polytropic relate to the type of cells that can be infected by the virus. For More recently, with the possibility of retroviruses this host tropism is largely pseudotyping viruses with non-retrovirus determined by the viral envelope glycoprotein derived glycoproteins, other terms such as and whether the target cells have an appropriate pantropic and dualtropic have been coined to receptor i.e. cellular entry involves interaction describe host range. For example retroviruses between the surface subunit of the virion pseudotyped with vesicular stomatitis virus envelope glycoprotein and cell-surface glycoprotein (VSV G) can infect most cultured determinants. The receptor binding triggers cell types resulting in these viruses being membrane fusion, mediated by transmembrane referred to as pantropic. Entry into cells is not subunits, resulting in delivery of the virus capsid dependant on the presence of a receptor because into the target cell. VSV G binds lipid and induces cell fusion to mediate virus infection. The widely used cell An ecotropic retrovirus is a retrovirus that will line PT76 expresses 10A1 an envelope grow in cells of the species from which it was glycoprotein from a murine leukaemia virus isolated, but to a very limited or undetectable which recognises two different receptors, the level in cells of other species, for example, amphotropic retrovirus receptor RAM 1 (Pit2) Friend murine leukaemia virus (FrMuLV). A and the gibbon ape leukaemia virus (GALV) xenotropic retrovirus is a retrovirus that does receptor (Pit1). Thus virus produced in PT76 or not produce disease in its natural host and stable virus producing derivatives of these cells replicates only in tissue culture cells derived can be thought of as dualtropic with an increased from a different species, for example, the murine host range relative to amphotropic viruses i.e. leukaemia virus NZB. An amphotropic two receptors for a virus to interact with means retrovirus will grow in the cells from which it that if one is not expressed at sufficient levels by a was isolated and also in cells from a wide range of given species or cell type, the other may still other species, for example, Moloney murine allow viral entry. Experimental use of leukaemia virus (MoMuLV). Other terms such pseudotyping with VSV-G has important safety implications that will be discussed in section 9.6. Table 3: Host Range of Viruses Expressing Various Types of Glycoprotein Target Viral Envelope Cell Origin Dualtropic Ecotropic Amphotropic Pantropic i.e. e.g. MLV 0A1* e.g. ga70 e.g. 4070A pseudotyped with VSV G Mouse + + + + Rat + + + + Hamster + – +/– + Mink + – + + Prepared by: Safety Office Approved by: Biosafety Committee Issue date October 2019 Retrovirus/Vectors guidance v3 Page 3 of 14 Review date October 2022 Table 3: Host Range of Viruses Expressing Various Types of Glycoprotein Target Viral Envelope Cell Origin Dualtropic Ecotropic Amphotropic Pantropic i.e. e.g. MLV 0A1* e.g. ga70 e.g. 4070A pseudotyped with VSV G Cat + – + + Dog + – + + Monkey + – + + Human + – + + Avian – – – + Fish – – – + Insect – – – + * Present on PT76 packaging cell line. Many other glycoproteins of viral and cellular occurs in conjunction with/within the core origin have been used to give novel target cell particle giving rise to a DNA provirus that specificities to retroviral vectors. Of particular contains a repeated U3, R and U5 at either end note is the RD114 envelope from a feline (i.e. the long terminal repeat – LTR). Proviral endogenous virus that has been shown to DNA migrates into the nucleus and inserts into transduce human haemopoetic stems cells i.e. the host chromosome where it can act as a CD34+ cells and may be useful for a number of template for viral mRNA and copies of the viral gene therapy applications. genome. Viral gene expression is regulated in part by the LTR’s that contain a strong viral 5. Virus Genome/Replication transcriptional promoter and enhancer regions (the U3 region). Retroviruses have a truly diploid genome consisting of 2 single stranded positive sense All retroviruses contain the same three gene RNA molecules which vary from 8-11Kb and clusters in the same order i.e. 5' - gag - pol - env - possess a 5' cap and 3' poly A. The RNA is 3'. gag codes for structural proteins, pol codes for hydrogen bonded and requires a specific cellular reverse transcriptase and integrase, while env tRNA (usually trp, pro or lys) for replication codes for the envelope glycoprotein’s. The more which is also packaged into the viral particle. complex families of retroviruses (delta- Although the genomic RNA is equivalent to retroviruses, spumaviruses and lentiviruses) have mRNA it does not become translated additional genes that affect various aspects of the immediately after infection probably because the viral life cycle. For example HIV vif appears to virus is only partially uncoated resulting in a enhance viral infectivity, rev acts as a post- core (nucleocapsid) particle in the cytoplasm. transcriptional activator of HIV gene Reverse transcription of the viral RNA genome transcription, while HIV tat enhances replication Prepared by: Safety Office Approved by: Biosafety Committee Issue date October 2019 Retrovirus/Vectors guidance v3 Page 4 of 14 Review date October 2022
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