Journal articles: 'Alpharetrovirus'

1

Suerth, Julia D., Tobias Maetzig, Melanie Galla, Christopher Baum, and Axel Schambach. "Self-Inactivating Alpharetroviral Vectors with a Split-Packaging Design." Journal of Virology 84, no. 13 (2010): 6626–35. http://dx.doi.org/10.1128/jvi.00182-10.

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ABSTRACT Accidental insertional activation of proto-oncogenes and potential vector mobilization pose serious challenges for human gene therapy using retroviral vectors. Comparative analyses of integration sites of different retroviral vectors have elucidated distinct target site preferences, highlighting vectors based on the alpharetrovirus Rous sarcoma virus (RSV) as those with the most neutral integration spectrum. To date, alpharetroviral vector systems are based mainly on single constructs containing viral coding sequences and intact long terminal repeats (LTR). Even though they are considered to be replication incompetent in mammalian cells, the transfer of intact viral genomes is unacceptable for clinical applications, due to the risk of vector mobilization and the potentially immunogenic expression of viral proteins, which we minimized by setting up a split-packaging system expressing the necessary viral proteins in trans. Moreover, intact LTRs containing transcriptional elements are capable of activating cellular genes. By removing most of these transcriptional elements, we were able to generate a self-inactivating (SIN) alpharetroviral vector, whose LTR transcriptional activity is strongly reduced and whose transgene expression can be driven by an internal promoter of choice. Codon optimization of the alpharetroviral Gag/Pol expression construct and further optimization steps allowed the production of high-titer self-inactivating vector particles in human cells. We demonstrate proof of principle for the versatility of alpharetroviral SIN vectors for the genetic modification of murine and human hematopoietic cells at a low multiplicity of infection.

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Wiegand, Heather L., and Bryan R. Cullen. "Inhibition of Alpharetrovirus Replication by a Range of Human APOBEC3 Proteins." Journal of Virology 81, no. 24 (2007): 13694–99. http://dx.doi.org/10.1128/jvi.01646-07.

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ABSTRACT The mammalian APOBEC3 family of cytidine deaminases includes members that can act as potent inhibitors of retroviral infectivity and retrotransposon mobility. Here, we have examined whether the alpharetrovirus Rous sarcoma virus (RSV) is susceptible to inhibition by a range of human APOBEC3 proteins. We report that RSV is highly susceptible to inhibition by human APOBEC3G, APOBEC3F, and APOBEC3B and moderately susceptible to inhibition by human APOBEC3C and APOBEC3A. For all five proteins, inhibition of RSV infectivity was associated with selective virion incorporation and with C-to-T editing of the proviral DNA minus strand. In the case of APOBEC3G, editing appeared to be critical for effective inhibition. These data represent the first report of inhibition of retroviral infectivity and induction of proviral DNA editing by human APOBEC3A and reveal that alpharetroviruses, which do not normally encounter APOBEC3 proteins in their avian hosts, are susceptible to inhibition by all human APOBEC3 proteins tested. These data further suggest that the resistance of mammalian retroviruses to inhibition by the APOBEC3 proteins expressed in their normal host species is likely to have evolved subsequent to the appearance of this family of mammalian antiretroviral proteins some 35 million years ago; i.e., the base state of a naïve retrovirus is susceptibility to inhibition.

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Rainey, G. Jonah A., and John M. Coffin. "Evolution of Broad Host Range in Retroviruses Leads to Cell Death Mediated by Highly Cytopathic Variants." Journal of Virology 80, no. 2 (2006): 562–70. http://dx.doi.org/10.1128/jvi.80.2.562-570.2006.

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ABSTRACT The ability of many retroviruses to cause disease can be correlated to their cytopathic effect (CPE) in tissue culture characterized by an acute period of cell death and viral DNA accumulation. Here, we show that mutants of a subgroup B avian retrovirus (Alpharetrovirus) cause a very dramatic CPE in certain susceptible avian cells that is coincident with elevated levels of apoptosis, as measured by nuclear morphology, and persistent viral DNA accumulation. These mutants also have a broadly extended host range that includes rodent, cat, dog, monkey, and human cells (31). Previously, we have shown that the mutants exhibit diminished resistance to superinfection. The results presented here have important implications for the process of evolution of retroviruses to use distinct cellular receptors.

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Butterfield-Gerson, Kristin L., Lisa Z. Scheifele, Eileen P. Ryan, Anita K. Hopper та Leslie J. Parent. "Importin-β Family Members Mediate Alpharetrovirus Gag Nuclear Entry via Interactions with Matrix and Nucleocapsid". Journal of Virology 80, № 4 (2006): 1798–806. http://dx.doi.org/10.1128/jvi.80.4.1798-1806.2006.

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ABSTRACT The retroviral Gag polyprotein orchestrates the assembly and release of virus particles from infected cells. We previously reported that nuclear transport of the Rous sarcoma virus (RSV) Gag protein is intrinsic to the virus assembly pathway. To identify cis- and trans-acting factors governing nucleocytoplasmic trafficking, we developed novel vectors to express regions of Gag in Saccharomyces cerevisiae. The localization of Gag proteins was examined in the wild type and in mutant strains deficient in members of the importin-β family. We confirmed the Crm1p dependence of the previously identified Gag p10 nuclear export signal. The known nuclear localization signal (NLS) in MA (matrix) was also functional in S. cerevisiae, and additionally we discovered a novel NLS within the NC (nucleocapsid) domain of Gag. MA utilizes Kap120p and Mtr10p import receptors while nuclear entry of NC involves the classical importin-α/β (Kap60p/95p) pathway. NC also possesses nuclear targeting activity in avian cells and contains the primary signal for the import of the Gag polyprotein. Thus, the nucleocytoplasmic dynamics of RSV Gag depend upon the counterbalance of Crm1p-mediated export with two independent NLSs, each interacting with distinct nuclear import factors.

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Obr, Martin, Florian K. M. Schur, and Robert A. Dick. "A Structural Perspective of the Role of IP6 in Immature and Mature Retroviral Assembly." Viruses 13, no. 9 (2021): 1853. http://dx.doi.org/10.3390/v13091853.

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The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.

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Harper, Amy L., Malgorzata Sudol, and Michael Katzman. "An Amino Acid in the Central Catalytic Domain of Three Retroviral Integrases That Affects Target Site Selection in Nonviral DNA." Journal of Virology 77, no. 6 (2003): 3838–45. http://dx.doi.org/10.1128/jvi.77.6.3838-3845.2003.

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ABSTRACT Integrase can insert retroviral DNA into almost any site in cellular DNA; however, target site preferences are noted in vitro and in vivo. We recently demonstrated that amino acid 119, in the α2 helix of the central domain of the human immunodeficiency virus type 1 integrase, affected the choice of nonviral target DNA sites. We have now extended these findings to the integrases of a nonprimate lentivirus and a more distantly related alpharetrovirus. We found that substitutions at the analogous positions in visna virus integrase and Rous sarcoma virus integrase changed the target site preferences in five assays that monitor insertion into nonviral DNA. Thus, the importance of this protein residue in the selection of nonviral target DNA sites is likely to be a general property of retroviral integrases. Moreover, this amino acid might be part of the cellular DNA binding site on integrase proteins.

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Lee, Eun-Gyung, and Maxine L. Linial. "Deletion of a Cys–His motif from the Alpharetrovirus nucleocapsid domain reveals late domain mutant-like budding defects." Virology 347, no. 1 (2006): 226–33. http://dx.doi.org/10.1016/j.virol.2005.11.048.

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8

Jouvenet, Nolwenn, Stuart J. D. Neil, Maria Zhadina, et al. "Broad-Spectrum Inhibition of Retroviral and Filoviral Particle Release by Tetherin." Journal of Virology 83, no. 4 (2008): 1837–44. http://dx.doi.org/10.1128/jvi.02211-08.

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ABSTRACT The expression of many putative antiviral genes is upregulated when cells encounter type I interferon (IFN), but the actual mechanisms by which many IFN-induced gene products inhibit virus replication are poorly understood. A recently identified IFN-induced antiretroviral protein, termed tetherin (previously known as BST-2 or CD317), blocks the release of nascent human immunodeficiency virus type 1 (HIV-1) particles from infected cells, and an HIV-1 accessory protein, Vpu, acts as a viral antagonist of tetherin. Here, we show that tetherin is capable of blocking not only the release of HIV-1 particles but also the release of particles assembled using the major structural proteins of a variety of prototype retroviruses, including members of the alpharetrovirus, betaretrovirus, deltaretrovirus, lentivirus, and spumaretrovirus families. Moreover, we show that the release of particles assembled using filovirus matrix proteins from Marburg virus and Ebola virus is also sensitive to inhibition by tetherin. These findings indicate that tetherin is a broadly specific inhibitor of enveloped particle release, and therefore, inhibition is unlikely to require specific interactions with viral proteins. Nonetheless, tetherin colocalized with nascent virus-like particles generated by several retroviral and filoviral structural proteins, indicating that it is present at, or recruited to, sites of particle assembly. Overall, tetherin is potentially active against many enveloped viruses and likely to be an important component of the antiviral innate immune defense.

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Derse, David, Bruce Crise, Yuan Li, et al. "Human T-Cell Leukemia Virus Type 1 Integration Target Sites in the Human Genome: Comparison with Those of Other Retroviruses." Journal of Virology 81, no. 12 (2007): 6731–41. http://dx.doi.org/10.1128/jvi.02752-06.

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ABSTRACT Retroviral integration into the host genome is not entirely random, and integration site preferences vary among different retroviruses. Human immunodeficiency virus (HIV) prefers to integrate within active genes, whereas murine leukemia virus (MLV) prefers to integrate near transcription start sites and CpG islands. On the other hand, integration of avian sarcoma-leukosis virus (ASLV) shows little preference either for genes, transcription start sites, or CpG islands. While host cellular factors play important roles in target site selection, the viral integrase is probably the major viral determinant. It is reasonable to hypothesize that retroviruses with similar integrases have similar preferences for target site selection. Although integration profiles are well defined for members of the lentivirus, spumaretrovirus, alpharetrovirus, and gammaretrovirus genera, no members of the deltaretroviruses, for example, human T-cell leukemia virus type 1 (HTLV-1), have been evaluated. We have mapped 541 HTLV-1 integration sites in human HeLa cells and show that HTLV-1, like ASLV, does not specifically target transcription units and transcription start sites. Comparing the integration sites of HTLV-1 with those of ASLV, HIV, simian immunodeficiency virus, MLV, and foamy virus, we show that global and local integration site preferences correlate with the sequence/structure of virus-encoded integrases, supporting the idea that integrase is the major determinant of retroviral integration site selection. Our results suggest that the global integration profiles of other retroviruses could be predicted from phylogenetic comparisons of the integrase proteins. Our results show that retroviruses that engender different insertional mutagenesis risks can have similar integration profiles.

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Lee, Eun-Gyung, та Maxine L. Linial. "Basic Residues of the Retroviral Nucleocapsid Play Different Roles in Gag-Gag and Gag-Ψ RNA Interactions". Journal of Virology 78, № 16 (2004): 8486–95. http://dx.doi.org/10.1128/jvi.78.16.8486-8495.2004.

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ABSTRACT The Orthoretrovirus Gag interaction (I) domain maps to the nucleocapsid (NC) domain in the Gag polyprotein. We used the yeast two-hybrid system to analyze the role of Alpharetrovirus NC in Gag-Gag interactions and also examined the efficiency of viral assembly and release in vivo. We could delete either or both of the two Cys-His (CH) boxes without abrogating Gag-Gag interactions. We found that as few as eight clustered basic residues, attached to the C terminus of the spacer peptide separating the capsid (CA) and NC domains in the absence of NC, was sufficient for Gag-Gag interactions. Our results support the idea that a sufficient number of basic residues, rather than the CH boxes, play the important role in Gag multimerization. We also examined the requirement for basic residues in Gag for packaging of specific packaging signal (Ψ)-containing RNA. Using a yeast three-hybrid RNA-protein interaction assay, second-site suppressors of a packaging-defective Gag mutant were isolated, which restored Ψ RNA binding. These suppressors mapped to the p10 or CA domains in Gag and resulted in either introduction of a positively charged residue or elimination of a negatively charged one. These results imply that the structural interactions of NC with other domains of Gag are necessary for Ψ RNA binding. Taken together, our results show that while Gag assembly only requires a certain number of positively charged amino acids, Gag binding to genomic RNA for packaging requires more complex interactions inherent in the protein tertiary structure.

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Morgan, Michael A., Arnold Kloos, Daniela Lenz, et al. "Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123." Viruses 13, no. 7 (2021): 1365. http://dx.doi.org/10.3390/v13071365.

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Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.

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Schambach, Axel. "Alpharetroviral self-inactivating vectors: an emerging tool for gene therapy." Cell and Gene Therapy Insights 2, no. 5 (2016): 623–27. http://dx.doi.org/10.18609/cgti.2016.070.

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Moiani, Arianna, Julia Suerth, Francesco Gandolfi, et al. "Genome-Wide Analysis of Alpharetroviral Integration in Human Hematopoietic Stem/Progenitor Cells." Genes 5, no. 2 (2014): 415–29. http://dx.doi.org/10.3390/genes5020415.

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Suerth, Julia D., Michael A. Morgan, Stephan Kloess, et al. "Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors." Journal of Molecular Medicine 94, no. 1 (2015): 83–93. http://dx.doi.org/10.1007/s00109-015-1327-6.

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Modlich, Ute, Julia Sürth, Daniela Zychlinski, et al. "Use of the in Vitro Immortalization Assay to Quantify the Impact of Integration Spectrum and Vector Design on Insertional Mutagenesis." Blood 118, no. 21 (2011): 3123. http://dx.doi.org/10.1182/blood.v118.21.3123.3123.

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Abstract Abstract 3123 In gene therapy targeting hematopoietic cells, a quantitative assessment of the risk factors underlying insertional mutagenesis is required to assess the practical value of preventive actions. Emanating from an observation of the Copeland lab (Du et al., 2005) we developed an in vitro immortalization (IVIM) assay which determines the risk of transformation of murine bone marrow cells as a consequence of insertional upregulation of Evi1 or Prdm16. These functionally related genes encode master regulators of hematopoiesis which are involved in the pathogenesis of human leukemia and insertional transformation in human gene therapy. Using our standardized conditions, the assay can detect mutants arising with a low frequency (down to 1 in a million cells), based on their rescue and expansion upon replating. The genetic lesion associated with clonal transformation is easily identified, and we can quantify not only the incidence of mutants (number of cells required to form a mutant) but also their fitness (number of subclones obtained by replating). Using the IVIM assay, our published work has revealed the following: (1) relocating gammaretroviral enhancer-promoter sequences from the LTR to an internal position of a “self-inactivating” (SIN) vector reduces the fitness of mutants, as do mutations in transcription factor binding sites or insulators that reduce the enhancer activity; (2) cellular promoters located in SIN vectors, depending on their enhancer activity, may reduce the risk of transformation below the detection limit (>3 logs compared to standard gammaretroviral vectors); (3) the post-transcriptional regulatory element of the woodchuck hepatitis virus does not affect insertional transformation; and (4) the lentiviral integration pattern reduces the risk of insertional transformation by a factor of ∼3 compared to gammaretroviral vectors. In the meantime, the assay has been used to assess the transforming potential of new vectors developed to treat a variety of hematopoietic disorders, most notably X-SCID, X-CGD, WAS and globinopathies. Reproducibly we found that vectors containing cellular promoters reduced the risk of insertional transformation when compared to retroviral promoters, although not all cellular promoters appeared to be free of risk. The assay has also revealed major functional differences of various insulator elements, including synthetic ones designed to block enhancer-crosstalk. Testing a battery of 8 insulators that we obtained from collaborators or designed ourselves, we found that only a subset was potent enough to significantly reduce the transforming potential of a strong retroviral enhancer-promoter. Furthermore, we assessed the transforming potential of our new alpharetroviral SIN vectors (Suerth et al., JV 2010), modified to remove a residual TATA box of the LTR. When containing a retroviral internal promoter, alpharetroviral SIN vectors were ∼9-times and 3-times, respectively, less likely than the corresponding gammaretroviral and lentiviral constructs to induce strongly replicating clones. Mutants obtained with alpharetroviral SIN vector insertions in Evi1 were not only less frequent but also had a greatly reduced fitness compared to those induced by similarly designed gammaretroviral vectors. Alpharetroviral SIN vectors containing the human elongation factor 1 alpha promoter did not immortalize cells in this assay, as previously shown for gammaretroviral SIN vectors. Finally, we performed experiments to explore the mechanistic basis of the IVIM assay. Our data suggest that its principle is the selection of mutants that resist the differentiation-inducing effect of a myeloid growth factor cocktail. Therefore, variations of the cell culture conditions have a significant impact on the sensitivity of the assay, and potentially also on the spectrum of mutants that can be isolated. The established conditions typically select for upregulation of Evi1, Prdm16, or, more rarely observed, Ras -related genes. In summary, the IVIM assay quantifies the risk of insertional mutagenesis in gene therapy, related to vector sequences and integration pattern. It is specifically useful to assess the risk of insertional upregulation of Evi1 and Prdm16 via enhancer-mediated mechanisms, in myeloid progenitor cells. It thus serves as an animal replacement assay to screen for safety-enhancing vector modifications. Disclosures: Off Label Use: CliniMACS for selection of CD34+ hematopoietic cells.

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Schott, Juliane W., Diego León-Rico, Carolina B. Ferreira, et al. "Enhancing Lentiviral and Alpharetroviral Transduction of Human Hematopoietic Stem Cells for Clinical Application." Molecular Therapy - Methods & Clinical Development 14 (September 2019): 134–47. http://dx.doi.org/10.1016/j.omtm.2019.05.015.

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Suerth, Julia, Verena Labenski, and Axel Schambach. "Alpharetroviral Vectors: From a Cancer-Causing Agent to a Useful Tool for Human Gene Therapy." Viruses 6, no. 12 (2014): 4811–38. http://dx.doi.org/10.3390/v6124811.

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Suerth, Julia D., Tobias Maetzig, Martijn H. Brugman, et al. "Alpharetroviral Self-inactivating Vectors: Long-term Transgene Expression in Murine Hematopoietic Cells and Low Genotoxicity." Molecular Therapy 20, no. 5 (2012): 1022–32. http://dx.doi.org/10.1038/mt.2011.309.

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Kaufmann, Kerstin B., Christian Brendel, Julia D. Suerth, et al. "Alpharetroviral Vector-mediated Gene Therapy for X-CGD: Functional Correction and Lack of Aberrant Splicing." Molecular Therapy 21, no. 3 (2013): 648–61. http://dx.doi.org/10.1038/mt.2012.249.

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Yin, Xueqian, Deborah C. Melder, William S. Payne, Jerry B. Dodgson, and Mark J. Federspiel. "Mutations in Both the Surface and Transmembrane Envelope Glycoproteins of the RAV-2 Subgroup B Avian Sarcoma and Leukosis Virus Are Required to Escape the Antiviral Effect of a Secreted Form of the TvbS3 Receptor †." Viruses 11, no. 6 (2019): 500. http://dx.doi.org/10.3390/v11060500.

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The subgroup A through E avian sarcoma and leukosis viruses ASLV(A) through ASLV(E) are a group of highly related alpharetroviruses that have evolved to use very different host protein families as receptors. We have exploited genetic selection strategies to force the replication-competent ASLVs to naturally evolve and acquire mutations to escape the pressure on virus entry and yield a functional replicating virus. In this study, evolutionary pressure was exerted on ASLV(B) virus entry and replication using a secreted for of its Tvb receptor. As expected, mutations in the ASLV(B) surface glycoprotein hypervariable regions were selected that knocked out the ability for the mutant glycoprotein to bind the sTvbS3-IgG inhibitor. However, the subgroup B Rous associated virus 2 (RAV-2) also required additional mutations in the C-terminal end of the SU glycoprotein and multiple regions of TM highlighting the importance of the entire viral envelope glycoprotein trimer structure to mediate the entry process efficiently. These mutations altered the normal two-step ASLV membrane fusion process to enable infection.

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Hübner, Juwita, Shahabuddin S. Hoseini, Julia D. Suerth, et al. "Generation of Genetically Engineered Precursor T-Cells From Human Umbilical Cord Blood Using an Optimized Alpharetroviral Vector Platform." Molecular Therapy 24, no. 7 (2016): 1216–26. http://dx.doi.org/10.1038/mt.2016.89.

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Munguia, Audelia, and Mark J. Federspiel. "Avian Sarcoma and Leukosis Virus Envelope Glycoproteins Evolve to Broaden Receptor Usage Under Pressure from Entry Competitors †." Viruses 11, no. 6 (2019): 519. http://dx.doi.org/10.3390/v11060519.

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The subgroup A through E avian sarcoma and leukosis viruses (ASLV(A) through ASLV(E)) are a group of highly related alpharetroviruses that have evolved their envelope glycoproteins to use different receptors to enable efficient virus entry due to host resistance and/or to expand host range. Previously, we demonstrated that ASLV(A) in the presence of a competitor to the subgroup A Tva receptor, SUA-rIgG immunoadhesin, evolved to use other receptor options. The selected mutant virus, RCASBP(A)Δ155–160, modestly expanded its use of the Tvb and Tvc receptors and possibly other cell surface proteins while maintaining the binding affinity to Tva. In this study, we further evolved the Δ155–160 virus with the genetic selection pressure of a soluble form of the Tva receptor that should force the loss of Tva binding affinity in the presence of the Δ155–160 mutation. Viable ASLVs were selected that acquired additional mutations in the Δ155–160 Env hypervariable regions that significantly broadened receptor usage to include Tvb and Tvc as well as retaining the use of Tva as a receptor determined by receptor interference assays. A similar deletion in the hr1 hypervariable region of the subgroup C ASLV glycoproteins evolved to broaden receptor usage when selected on Tvc-negative cells.

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Gifford, Robert, Peter Kabat, Joanne Martin, Clare Lynch, and Michael Tristem. "Evolution and Distribution of Class II-Related Endogenous Retroviruses." Journal of Virology 79, no. 10 (2005): 6478–86. http://dx.doi.org/10.1128/jvi.79.10.6478-6486.2005.

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ABSTRACT Endogenous retroviruses (ERVs) are widespread in vertebrate genomes and have been loosely grouped into “classes” on the basis of their phylogenetic relatedness to the established genera of exogenous retroviruses. Four of these genera—the lentiviruses, alpharetroviruses, betaretroviruses, and deltaretroviruses—form a well-supported clade in retroviral phylogenies, and ERVs that group with these genera have been termed class II ERVs. We used PCR amplification and sequencing of retroviral fragments from more than 130 vertebrate taxa to investigate the evolution of the class II retroviruses in detail. We confirm that class II retroviruses are largely confined to mammalian and avian hosts and provide evidence for a major novel group of avian retroviruses, and we identify additional members of both the alpha- and the betaretrovirus genera. Phylogenetic analyses demonstrated that the avian and mammalian viruses form distinct monophyletic groups, implying that interclass transmission has occurred only rarely during the evolution of the class II retroviruses. In contrast to previous reports, the lentiviruses clustered as sister taxa to several endogenous retroviruses derived from rodents and insectivores. This topology was further supported by the shared loss of both the class II PR-Pol frameshift site and the class II retrovirus G-patch domain.

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Labenski, Verena, Julia D. Suerth, Elke Barczak, et al. "Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes." Biomaterials 97 (August 2016): 97–109. http://dx.doi.org/10.1016/j.biomaterials.2016.04.019.

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de Marco, Alex, Norman E. Davey, Pavel Ulbrich, et al. "Conserved and Variable Features of Gag Structure and Arrangement in Immature Retrovirus Particles." Journal of Virology 84, no. 22 (2010): 11729–36. http://dx.doi.org/10.1128/jvi.01423-10.

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ABSTRACT The assembly of retroviruses is driven by oligomerization of the Gag polyprotein. We have used cryo-electron tomography together with subtomogram averaging to describe the three-dimensional structure of in vitro-assembled Gag particles from human immunodeficiency virus, Mason-Pfizer monkey virus, and Rous sarcoma virus. These represent three different retroviral genera: the lentiviruses, betaretroviruses and alpharetroviruses. Comparison of the three structures reveals the features of the supramolecular organization of Gag that are conserved between genera and therefore reflect general principles of Gag-Gag interactions and the features that are specific to certain genera. All three Gag proteins assemble to form approximately spherical hexameric lattices with irregular defects. In all three genera, the N-terminal domain of CA is arranged in hexameric rings around large holes. Where the rings meet, 2-fold densities, assigned to the C-terminal domain of CA, extend between adjacent rings, and link together at the 6-fold symmetry axis with a density, which extends toward the center of the particle into the nucleic acid layer. Although this general arrangement is conserved, differences can be seen throughout the CA and spacer peptide regions. These differences can be related to sequence differences among the genera. We conclude that the arrangement of the structural domains of CA is well conserved across genera, whereas the relationship between CA, the spacer peptide region, and the nucleic acid is more specific to each genus.

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Oberschmidt, Olaf, Michael Morgan, Volker Huppert, et al. "Development of Automated Separation, Expansion, and Quality Control Protocols for Clinical-Scale Manufacturing of Primary Human NK Cells and Alpharetroviral Chimeric Antigen Receptor Engineering." Human Gene Therapy Methods 30, no. 3 (2019): 102–20. http://dx.doi.org/10.1089/hgtb.2019.039.

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Rainey, G. Jonah A., Andrew Natonson, Lori F. Maxfield, and John M. Coffin. "Mechanisms of Avian Retroviral Host Range Extension." Journal of Virology 77, no. 12 (2003): 6709–19. http://dx.doi.org/10.1128/jvi.77.12.6709-6719.2003.

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ABSTRACT Alpharetroviruses provide a useful system for the study of the molecular mechanisms of host range and receptor interaction. These viruses can be divided into subgroups based on diverse receptor usage due to variability within the two host range determining regions, hr1 and hr2, in their envelope glycoprotein SU (gp85). In previous work, our laboratory described selection from a subgroup B avian sarcoma-leukosis virus of an extended-host-range variant (LT/SI) with two adjacent amino acid substitutions in hr1. This virus retains its ability to use the subgroup BD receptor but can also infect QT6/BD cells, which bear a related subgroup E receptor (R. A. Taplitz and J. M. Coffin, J. Virol 71:7814-7819, 1997). Here, we report further analysis of this unusual variant. First, one (L154S) of the two substitutions is sufficient for host range extension, while the other (T155I) does not alter host range. Second, these mutations extend host range to non-avian cell types, including human, dog, cat, mouse, rat, and hamster. Third, interference experiments imply that the mutants interact efficiently with the subgroup BD receptor and possibly the related subgroup E receptor, but they have another means of entry that is not dependent on these interactions. Fourth, binding studies indicate that the mutant SU proteins retain the ability to interact as monomers with subgroup BD and BDE receptors but only bind the subgroup E receptor in the context of an Env trimer. Further, the mutant SU proteins bind well to chicken cells but do not bind any better than wild-type subgroup B to QT6 or human cells, even though the corresponding viruses are capable of infecting these cells.

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Dostálková, Alžběta, Barbora Vokatá, Filip Kaufman, Pavel Ulbrich, Tomáš Ruml, and Michaela Rumlová. "Effect of Small Polyanions on In Vitro Assembly of Selected Members of Alpha-, Beta- and Gammaretroviruses." Viruses 13, no. 1 (2021): 129. http://dx.doi.org/10.3390/v13010129.

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The assembly of a hexameric lattice of retroviral immature particles requires the involvement of cell factors such as proteins and small molecules. A small, negatively charged polyanionic molecule, myo-inositol hexaphosphate (IP6), was identified to stimulate the assembly of immature particles of HIV-1 and other lentiviruses. Interestingly, cryo-electron tomography analysis of the immature particles of two lentiviruses, HIV-1 and equine infectious anemia virus (EIAV), revealed that the IP6 binding site is similar. Based on this amino acid conservation of the IP6 interacting site, it is presumed that the assembly of immature particles of all lentiviruses is stimulated by IP6. Although this specific region for IP6 binding may be unique for lentiviruses, it is plausible that other retroviral species also recruit some small polyanion to facilitate the assembly of their immature particles. To study whether the assembly of retroviruses other than lentiviruses can be stimulated by polyanionic molecules, we measured the effect of various polyanions on the assembly of immature virus-like particles of Rous sarcoma virus (RSV), a member of alpharetroviruses, Mason-Pfizer monkey virus (M-PMV) representative of betaretroviruses, and murine leukemia virus (MLV), a member of gammaretroviruses. RSV, M-PMV and MLV immature virus-like particles were assembled in vitro from truncated Gag molecules and the effect of selected polyanions, myo-inostol hexaphosphate, myo-inositol, glucose-1,6-bisphosphate, myo-inositol hexasulphate, and mellitic acid, on the particles assembly was quantified. Our results suggest that the assembly of immature particles of RSV and MLV was indeed stimulated by the presence of myo-inostol hexaphosphate and myo-inositol, respectively. In contrast, no effect on the assembly of M-PMV as a betaretrovirus member was observed.

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Zhang, Yao, Mengmeng Yu, Lixiao Xing, et al. "The Bipartite Sequence Motif in the N and C Termini of gp85 of Subgroup J Avian Leukosis Virus Plays a Crucial Role in Receptor Binding and Viral Entry." Journal of Virology 94, no. 22 (2020). http://dx.doi.org/10.1128/jvi.01232-20.

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ABSTRACT Subgroup J avian leukemia virus (ALV-J), belonging to the genus Alpharetrovirus, enters cells through its envelope surface unit (gp85) via specifically recognizing the cellular receptor chicken Na+/H+ exchanger type I (chNHE1), the 28 to 39 N-terminal residues of which were characterized as the minimal receptor functional domain in our previous studies. In this study, to further clarify the precise organization and properties of the interaction between ALV-J gp85 and chNHE1, we identified the chNHE1-binding domain of ALV-J gp85 using a series of gp85 mutants with segment substitutions and evaluating their effects on chNHE1 binding in protein-cell binding assays. Our results showed that hemagglutinin (HA) substitutions of amino acids (aa) 38 to 131 (N terminus of gp85) and aa 159 to 283 (C terminus of gp85) significantly inhibited the interaction between gp85 and chNHE1/chNHE1 loop 1. In addition, these HA-substituted chimeric gp85 proteins could not effectively block the entry of ALV-J into chNHE1-expressing cells. Furthermore, analysis of various N-linked glycosylation sites and cysteine mutants in gp85 revealed that glycosylation sites (N6 and N11) and cysteines (C3 and C9) were directly involved in receptor-gp85 binding and important for the entry of ALV-J into cells. Taken together, our findings indicated that the bipartite sequence motif, spanning aa 38 to 131 and aa 159 to 283, of ALV-J gp85 was essential for binding to chNHE1, with its two N-linked glycosylation sites and two cysteines being important for its receptor-binding function and subsequent viral infection steps. IMPORTANCE Infection of a cell by retroviruses requires the attachment and fusion of the host and viral membranes. The specific adsorption of envelope (Env) surface proteins to cell receptors is a key step in triggering infections and has been the target of antiviral drug screening. ALV-J is an economically important avian pathogen that belongs to the genus Alpharetrovirus and has a wider host range than other ALV subgroups. Our results showed that the amino acids 38 to 131 of the N terminus and 159 to 283 of the C terminus of ALV-J gp85 controlled the efficiency of gp85 binding to chNHE1 and were critical for viral infection. In addition, the glycosylation sites (N6 and N11) and cysteines (C3 and C9) of gp85 played a crucial role in the receptor binding and viral entry. These findings might help elucidate the mechanism of the entry of ALV-J into host cells and provide antiviral targets for the control of ALV-J.

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Rice, Breanna L., Matthew S. Stake, and Leslie J. Parent. "TNPO3-Mediated Nuclear Entry of the Rous Sarcoma Virus Gag Protein Is Independent of the Cargo-Binding Domain." Journal of Virology 94, no. 17 (2020). http://dx.doi.org/10.1128/jvi.00640-20.

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ABSTRACT Retroviral Gag polyproteins orchestrate the assembly and release of nascent virus particles from the plasma membranes of infected cells. Although it was traditionally thought that Gag proteins trafficked directly from the cytosol to the plasma membrane, we discovered that the oncogenic avian alpharetrovirus Rous sarcoma virus (RSV) Gag protein undergoes transient nucleocytoplasmic transport as an intrinsic step in virus assembly. Using a genetic approach in yeast, we identified three karyopherins that engage the two independent nuclear localization signals (NLSs) in Gag. The primary NLS is in the nucleocapsid (NC) domain of Gag and binds directly to importin-α, which recruits importin-β to mediate nuclear entry. The second NLS (TNPO3), which resides in the matrix (MA) domain, is dependent on importin-11 and transportin-3 (TNPO3), which are known as MTR10p and Kap120p in yeast, although it is not clear whether these import factors are independent or additive. The functions of importin-α/importin-β and importin-11 have been verified in avian cells, whereas the role of TNPO3 has not been studied. In this report, we demonstrate that TNPO3 directly binds to Gag and mediates its nuclear entry. To our surprise, this interaction did not require the cargo-binding domain (CBD) of TNPO3, which typically mediates nuclear entry for other binding partners of TNPO3, including SR domain-containing splicing factors and tRNAs that reenter the nucleus. These results suggest that RSV hijacks this host nuclear import pathway using a unique mechanism, potentially allowing other cargo to simultaneously bind TNPO3. IMPORTANCE RSV Gag nuclear entry is facilitated using three distinct host import factors that interact with nuclear localization signals in the Gag MA and NC domains. Here, we show that the MA region is required for nuclear import of Gag through the TNPO3 pathway. Gag nuclear entry does not require the CBD of TNPO3. Understanding the molecular basis for TNPO3-mediated nuclear trafficking of the RSV Gag protein may lead to a deeper appreciation for whether different import factors play distinct roles in retrovirus replication.

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Bolisetty, Mohan, Jonas Blomberg, Farid Benachenhou, Göran Sperber, and Karen Beemon. "Unexpected Diversity and Expression of Avian Endogenous Retroviruses." mBio 3, no. 5 (2012). http://dx.doi.org/10.1128/mbio.00344-12.

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ABSTRACTEndogenous retroviruses (ERVs) were identified and characterized in three avian genomes to gain insight into early retroviral evolution. Using the computer program RetroTector to detect relatively intact ERVs, we identified 500 ERVs in the chicken genome, 150 in the turkey genome, and 1,200 in the zebra finch genome. Previous studies suggested that endogenous alpharetroviruses were present in chicken genomes. In this analysis, a small number of alpharetroviruses were seen in the chicken and turkey genomes; however, these were greatly outnumbered by beta-like, gamma-like, and alphabeta proviruses. While the avian ERVs belonged to the same major groups as mammalian ERVs, they were more heterogeneous. In particular, the beta-like viruses revealed an evolutionary continuum with the gradual acquisition and loss of betaretroviral markers and a transition from beta to alphabeta and then to alpharetroviruses. Thus, it appears that birds may resemble a melting pot for early ERV evolution. Many of the ERVs were integrated in clusters on chromosomes, often near centromeres. About 25% of the chicken ERVs were in or near cellular transcription units; this is nearly random. The majority of these integrations were in the sense orientation in introns. A higher-than-random number of integrations were >100 kb from the nearest gene. Deep-sequencing studies of chicken embryo fibroblasts revealed that about 20% of the 500 ERVs were transcribed and translated. A subset of these were also transcribedin vivoin chickens, showing tissue-specific patterns of expression.IMPORTANCEStudies of avian endogenous retroviruses (ERVs) have given us a glimpse of an earlier retroviral world. Three different classes of ERVs were observed with many features of mammalian retroviruses, as well as some important differences. Many avian ERVs were transcribed and translated.

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"304. Self-Inactivating Alpharetroviral Vectors with a Split-Packaging Design." Molecular Therapy 18 (May 2010): S116—S117. http://dx.doi.org/10.1016/s1525-0016(16)37745-0.

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"348. Alpharetroviral SIN Vectors: Evaluation of Genotoxicity and Long-Term Expression in Hematopoiesis." Molecular Therapy 19 (May 2011): S135. http://dx.doi.org/10.1016/s1525-0016(16)36920-9.

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Hübner, J., SS Hoseini, JD Suerth, et al. "Engineered precursor T cells from human umbilical cord blood using an alpharetroviral vector platform." Klinische Pädiatrie 228, no. 03 (2016). http://dx.doi.org/10.1055/s-0036-1582502.

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Rice, Breanna L., Rebecca J. Kaddis, Matthew S. Stake, Timothy L. Lochmann, and Leslie J. Parent. "Interplay between the alpharetroviral Gag protein and SR proteins SF2 and SC35 in the nucleus." Frontiers in Microbiology 6 (September 8, 2015). http://dx.doi.org/10.3389/fmicb.2015.00925.

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"66. Rescue of the X-CGD Phenotype by an Alpharetroviral Vector without Concomitant Induction of Aberrant Splicing." Molecular Therapy 21 (May 2013): S27. http://dx.doi.org/10.1016/s1525-0016(16)34401-x.

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Winans, Shelby, Ross C. Larue, Carly M. Abraham, et al. "The FACT Complex Promotes Avian Leukosis Virus DNA Integration." Journal of Virology 91, no. 7 (2017). http://dx.doi.org/10.1128/jvi.00082-17.

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ABSTRACT All retroviruses need to integrate a DNA copy of their genome into the host chromatin. Cellular proteins regulating and targeting lentiviral and gammaretroviral integration in infected cells have been discovered, but the factors that mediate alpharetroviral avian leukosis virus (ALV) integration are unknown. In this study, we have identified the FACT protein complex, which consists of SSRP1 and Spt16, as a principal cellular binding partner of ALV integrase (IN). Biochemical experiments with purified recombinant proteins show that SSRP1 and Spt16 are able to individually bind ALV IN, but only the FACT complex effectively stimulates ALV integration activity in vitro. Likewise, in infected cells, the FACT complex promotes ALV integration activity, with proviral integration frequency varying directly with cellular expression levels of the FACT complex. An increase in 2-long-terminal-repeat (2-LTR) circles in the depleted FACT complex cell line indicates that this complex regulates the ALV life cycle at the level of integration. This regulation is shown to be specific to ALV, as disruption of the FACT complex did not inhibit either lentiviral or gammaretroviral integration in infected cells. IMPORTANCE The majority of human gene therapy approaches utilize HIV-1- or murine leukemia virus (MLV)-based vectors, which preferentially integrate near genes and regulatory regions; thus, insertional mutagenesis is a substantial risk. In contrast, ALV integrates more randomly throughout the genome, which decreases the risks of deleterious integration. Understanding how ALV integration is regulated could facilitate the development of ALV-based vectors for use in human gene therapy. Here we show that the FACT complex directly binds and regulates ALV integration efficiency in vitro and in infected cells.

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Journal articles on the topic 'Alpharetrovirus'

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