Escape from R-peptide deletion in a γ-retrovirus

Schneider, Irene C.; Eckhardt, Manon; Brynza, Julia; Collins, Mary; Cichutek, Klaus; Buchholz, Christian J.

doi:10.1016/j.virol.2011.07.011

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…However, while the production of LVs pseudotyped with 4070A has no impact on infectious titers,23, 24, 25, 26, 27 the co-expression of HIV-1 core proteins with GaLV or RD114 glycoproteins barely results in the production of infectious LVs 28, 29, 30, 31, 32. These titer asymmetries are due to differences between cytoplasmatic tail amino-acid sequences of the glycoproteins (Figure 1A), since the fully fusogenic activation of 4070A, RD114, and GaLV is dependent on the cytoplasmatic tail R-peptide recognition and cleavage by the viral protease 33, 34, 35, 36, 37, 38, 39, 40, 41, 42. The replacement of the RD114 and GaLV cytoplasmic tail region by the one for 4070A (originating the RD114-TR and GaLV-TR, respectively) allows a high increase of LV particle infectivity 19, 23, 28, 29, 31, 32.…”

Section: Introductionmentioning

confidence: 99%

Improved GaLV-TR Glycoproteins to Pseudotype Lentiviral Vectors: Impact of Viral Protease Activity in the Production of LV Pseudotypes

Tomás

Mestre

Rodrigues

et al. 2019

Molecular Therapy - Methods & Clinical Development

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Lentiviral vectors (LVs) are excellent tools for gene transfer into mammalian cells. It is noteworthy that the first gene therapy treatment using LVs was approved for commercialization in 2017. The G glycoprotein from rhabdovirus vesicular stomatitis virus (VSV-G) is the glycoprotein most used to pseudotype LVs, due to its high efficiency in transducing several cell types and its resistance to viral vector purification and storage conditions. However, VSV-G expression induces cytotoxicity, which limits LV production to short periods. As alternative to VSV-G, γ-retrovirus glycoproteins (4070A derived, GaLV derived, and RD114 derived) have been used to pseudotype both γ-retroviral vectors (RVs) and LVs. These glycoproteins do not induce cytotoxicity, allowing the development of stable LV producer cells. Additionally, these LV pseudotypes present higher transduction efficiencies of hematopoietic stem cells when compared to VSV-G. Here, new 4070A-, RD114-TR-, and GaLV-TR-derived glycoproteins were developed with the aim of improving its cytoplasmic tail R-peptide cleavage and thus increase LV infectious titers. The new glycoproteins were tested in transient LV production using the wild-type or the less active T26S HIV-1 protease. The GaLV-TR-derived glycoproteins were able to overcome titer differences observed between LV production using wild-type and T26S protease. Additionally, these glycoproteins were even able to increase LV titers, evidencing its potential as an alternative glycoprotein to pseudotype LVs.

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Section: Introductionmentioning

confidence: 99%

Improved GaLV-TR Glycoproteins to Pseudotype Lentiviral Vectors: Impact of Viral Protease Activity in the Production of LV Pseudotypes

Tomás

Mestre

Rodrigues

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…When the R-peptide was removed from a gammaretroviral Env it spread poorly in cell culture, but given time it acquired a compensatory extension of the C-terminus. This also restored the colocalization between the envelope protein and Gag, implying an additional role for the R-peptide in assembly of viral particles [ 170 ]. The R-peptide of MLV, and the entire cytoplasmic tail, is dispensable for assembly with HIV particles, consistent with the fact that HIV glycoproteins do not contain an R-peptide.…”

Section: Hallmark Features Of Gamma-type Envsmentioning

confidence: 99%

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

Hogan

Johnson

2023

Viruses

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After the onset of the AIDS pandemic, HIV-1 (genus Lentivirus) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the Alpharetrovirus, Gammaretrovirus and Deltaretrovirus genera. For example, oncogenic model system viruses such as Rous sarcoma virus (RSV, Alpharetrovirus), murine leukemia virus (MLV, Gammaretrovirus) and human T-cell leukemia viruses (HTLV-I and HTLV-II, Deltaretrovirus) encode Envs that are structurally and functionally distinct from HIV Env. We refer to these as Gamma-type Envs. Gamma-type Envs are probably the most widespread retroviral Envs in nature. They are found in exogenous and endogenous retroviruses representing a broad spectrum of vertebrate hosts including amphibians, birds, reptiles, mammals and fish. In endogenous form, gamma-type Envs have been evolutionarily coopted numerous times, most notably as placental syncytins (e.g., human SYNC1 and SYNC2). Remarkably, gamma-type Envs are also found outside of the Retroviridae. Gp2 proteins of filoviruses (e.g., Ebolavirus) and snake arenaviruses in the genus Reptarenavirus are gamma-type Env homologs, products of ancient recombination events involving viruses of different Baltimore classes. Distinctive hallmarks of gamma-type Envs include a labile disulfide bond linking the surface and transmembrane subunits, a multi-stage attachment and fusion mechanism, a highly conserved (but poorly understood) “immunosuppressive domain”, and activation by the viral protease during virion maturation. Here, we synthesize work from diverse retrovirus model systems to illustrate these distinctive properties and to highlight avenues for further exploration of gamma-type Env structure and function.

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“…As mentioned before, CT interactions with the viral core may play an important role in glycoprotein incorporation. It was shown that most mammalian and avian retroviruses such as HIV, MLV and ALV (avian leukemia virus) require proteolytic cleavage of the R-peptide, a short amino acid sequence (16 aa) at the C-terminus of CT of the envelope glycoprotein for activation (Bobkova et al, 2002;Green et al, 1981;Henderson et al, 1984;Schneider et al, 2011).…”

Section: Figure 6: Pseudotyping Of Lentiviral Vectorsmentioning

confidence: 99%

Targeted lentiviral vectors pseudotyped with the Tupaia paramyxovirus glycoproteins

et al. 2012

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Lentiviral vectors are vectors of choice for many gene therapy applications. Recently, efficient targeting of lentiviral vectors pseudotyped with the Measles virus (MV) glycoproteins has been reported. However, MV antibodies in patients might limit the clinical use of these vectors. We demonstrate here that lentiviral vectors can also be pseudotyped with the glycoproteins of Tupaia paramyxovirus (TPMV), the hemagglutinin (H) and fusion (F) protein. As this animal paramyxovirus has no known close relatives in humans, we do not expect TPMV antibodies in patients. Because TPMV normally does not infect human cells, 'detargeting' from natural receptors is unnecessary. Similar to the MV system, TPMV glycoproteins can mediate targeted cell entry by displaying different single-chain antibodies (scAb) directed against surface molecules on target cells on the viral hemagglutinin. We generated a panel of H and F proteins with truncated cytoplasmic tails and determined the variants that efficiently pseudotyped lentiviral vectors. The B-cell marker CD20 was used as a model antigen, and CD20-targeted TPMV vectors selectively transduced CD20-positive cells, including quiescent primary human B-cells. Lentiviral vectors pseudotyped with targeted TPMV envelope proteins might be a valuable vector choice when systemic application of targeted lentiviral vectors in humans is required.

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Escape from R-peptide deletion in a γ-retrovirus

Cited by 4 publications

References 26 publications

Improved GaLV-TR Glycoproteins to Pseudotype Lentiviral Vectors: Impact of Viral Protease Activity in the Production of LV Pseudotypes

Improved GaLV-TR Glycoproteins to Pseudotype Lentiviral Vectors: Impact of Viral Protease Activity in the Production of LV Pseudotypes

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

Targeted lentiviral vectors pseudotyped with the Tupaia paramyxovirus glycoproteins

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