scholarly journals Sequence Determinants in Gammaretroviral Env Cytoplasmic Tails Dictate Virus-Specific Pseudotyping Compatibility

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Yul Eum Song ◽  
Grace Y. Olinger ◽  
Sanath Kumar Janaka ◽  
Marc C. Johnson
Keyword(s):  
Viral Vectors ◽  
Leukemia Virus ◽  
Target Cells ◽  
Gag Protein ◽  
Factors Affecting ◽  
Gene Therapies ◽  
Viral Glycoproteins ◽  
Cytoplasmic Tails ◽  
Specific Manner ◽  
Hiv 1

ABSTRACTViruses can incorporate foreign glycoproteins to form infectious particles through a process known as pseudotyping. However, not all glycoproteins are compatible with all viruses. Despite the fact that viral pseudotyping is widely used, what makes a virus/glycoprotein pair compatible is poorly understood. To study this, we chose to analyze a gammaretroviral glycoprotein (Env) whose compatibility with different viruses could be modulated through small changes in its cytoplasmic tail (CT). One form of this glycoprotein is compatible with murine leukemia virus (MLV) particles but incompatible with human immunodeficiency virus type 1 (HIV-1) particles, while the second is compatible with HIV-1 particles but not with MLV particles. To decipher the factors affecting virus-specific Env incompatibility, we characterized Env incorporation, maturation, cell-to-cell fusogenicity, and virus-to-cell fusogenicity of each Env. The HIV-1 particle incompatibility correlated with less efficient cleavage of the R peptide by HIV-1 protease. However, the MLV particle incompatibility was more nuanced. MLV incompatibility appeared to be caused by lack of incorporation into particles, yet incorporation could be restored by further truncating the CT or by using a chimeric MLV Gag protein containing the HIV-1 MA without fully restoring infectivity. The MLV particle incompatibility appeared to be caused in part by fusogenic repression in MLV particles through an unknown mechanism. This study demonstrates that the Env CT can dictate functionality of Env within particles in a virus-specific manner.IMPORTANCEViruses utilize viral glycoproteins to efficiently enter target cells during infection. How viruses acquire viral glycoproteins has been studied to understand the pathogenesis of viruses and develop safer and more efficient viral vectors for gene therapies. The CTs of viral glycoproteins have been shown to regulate various stages of glycoprotein biogenesis, but a gap still remains in understanding the molecular mechanism of glycoprotein acquisition and functionality regarding the CT. Here, we studied the mechanism of how specific mutations in the CT of a gammaretroviral envelope glycoprotein distinctly affect infectivity of two different viruses. Different mutations caused failure of glycoproteins to function in a virus-specific manner due to distinct fusion defects, suggesting that there are virus-specific characteristics affecting glycoprotein functionality.

scholarly journals The versatile role of exosomes in human retroviral infections: from immunopathogenesis to clinical application

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jafar Rezaie ◽  
Cynthia Aslan ◽  
Mahdi Ahmadi ◽  
Naime Majidi Zolbanin ◽  
Fatah Kashanchi ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Biological Fluids ◽  
Recipient Cell ◽  
Leukemia Virus ◽  
Target Cells ◽  
Modern Approach ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Infected Cells ◽  
Hiv 1

AbstractEukaryotic cells produce extracellular vesicles (EVs) mediating intercellular communication. These vesicles encompass many bio-molecules such as proteins, nucleic acids, and lipids that are transported between cells and regulate pathophysiological actions in the recipient cell. Exosomes originate from multivesicular bodies inside cells and microvesicles shed from the plasma membrane and participate in various pathological conditions. Retroviruses such as Human Immunodeficiency Virus -type 1 (HIV-1) and Human T-cell leukemia virus (HTLV)-1 engage exosomes for spreading and infection. Exosomes from virus-infected cells transfer viral components such as miRNAs and proteins that promote infection and inflammation. Additionally, these exosomes deliver virus receptors to target cells that make them susceptible to virus entry. HIV-1 infected cells release exosomes that contribute to the pathogenesis including neurological disorders and malignancy. Exosomes can also potentially carry out as a modern approach for the development of HIV-1 and HTLV-1 vaccines. Furthermore, as exosomes are present in most biological fluids, they hold the supreme capacity for clinical usage in the early diagnosis and prognosis of viral infection and associated diseases. Our current knowledge of exosomes' role from virus-infected cells may provide an avenue for efficient retroviruses associated with disease prevention. However, the exact mechanism involved in retroviruses infection/ inflammation remains elusive and related exosomes research will shed light on the mechanisms of pathogenesis.

scholarly journals Selective and Nonselective Packaging of Cellular RNAs in Retrovirus Particles

2007 ◽  
Vol 81 (12) ◽  
pp. 6623-6631 ◽  
Author(s):  
Samuel J. Rulli ◽  
Catherine S. Hibbert ◽  
Jane Mirro ◽  
Thoru Pederson ◽  
Shyam Biswal ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Signal Recognition Particle ◽  
Viral Rna ◽  
Genomic Rna ◽  
Gag Protein ◽  
Mrna Species ◽  
Reverse Transcription Pcr ◽  
Cellular Mrnas ◽  
A Minor ◽  
Hiv 1

ABSTRACT Assembly of retrovirus particles normally entails the selective encapsidation of viral genomic RNA. However, in the absence of packageable viral RNA, assembly is still efficient, and the released virus-like particles (termed “Ψ−” particles) still contain roughly normal amounts of RNA. We have proposed that cellular mRNAs replace the genome in Ψ− particles. We have now analyzed the mRNA content of Ψ− and Ψ+ murine leukemia virus (MLV) particles using both microarray analysis and real-time reverse transcription-PCR. The majority of mRNA species present in the virus-producing cells were also detected in Ψ− particles. Remarkably, nearly all of them were packaged nonselectively; that is, their representation in the particles was simply proportional to their representation in the cells. However, a small number of low-abundance mRNAs were greatly enriched in the particles. In fact, one mRNA species was enriched to the same degree as Ψ+ genomic RNA. Similar results were obtained with particles formed from the human immunodeficiency virus type 1 (HIV-1) Gag protein, and the same mRNAs were enriched in MLV and HIV-1 particles. The levels of individual cellular mRNAs were ∼5- to 10-fold higher in Ψ− than in Ψ+ MLV particles, in agreement with the idea that they are replacing viral RNA in the former. In contrast, signal recognition particle RNA was present at the same level in Ψ− and Ψ+ particles; a minor fraction of this RNA was weakly associated with genomic RNA in Ψ+ MLV particles.

scholarly journals PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells

2020 ◽  
Vol 117 (17) ◽  
pp. 9537-9545 ◽  
Author(s):  
Yajing Fu ◽  
Sijia He ◽  
Abdul A. Waheed ◽  
Deemah Dabbagh ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Virus Particle ◽  
Influenza A ◽  
Leukemia Virus ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Selectin Binding ◽  
Anti Hiv ◽  
Hiv 1

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1–mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti–HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1–related monomeric E-selectin–binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1–mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.

scholarly journals Foreign Glycoproteins Can Be Actively Recruited to Virus Assembly Sites during Pseudotyping

2009 ◽  
Vol 83 (9) ◽  
pp. 4060-4067 ◽  
Author(s):  
Rebecca L. Jorgenson ◽  
Volker M. Vogt ◽  
Marc C. Johnson
Keyword(s):  
Plasma Membrane ◽  
Virus Assembly ◽  
Leukemia Virus ◽  
Viral Assembly ◽  
Surface Glycoprotein ◽  
Viral Budding ◽  
Rous Sarcoma ◽  
Viral Glycoproteins ◽  
Sarcoma Virus ◽  
Hiv 1

ABSTRACT Retroviruses like human immunodeficiency virus type 1 (HIV-1), as well as many other enveloped viruses, can efficiently produce infectious virus in the absence of their own surface glycoprotein if a suitable glycoprotein from a foreign virus is expressed in the same cell. This process of complementation, known as pseudotyping, often can occur even when the glycoprotein is from an unrelated virus. Although pseudotyping is widely used for engineering chimeric viruses, it has remained unknown whether a virus can actively recruit foreign glycoproteins to budding sites or, alternatively, if a virus obtains the glycoproteins through a passive mechanism. We have studied the specificity of glycoprotein recruitment by immunogold labeling viral glycoproteins and imaging their distribution on the host plasma membrane using scanning electron microscopy. Expressed alone, all tested viral glycoproteins were relatively randomly distributed on the plasma membrane. However, in the presence of budding HIV-1 or Rous sarcoma virus (RSV) particles, some glycoproteins, such as those encoded by murine leukemia virus and vesicular stomatitis virus, were dramatically redistributed to viral budding sites. In contrast, the RSV Env glycoprotein was robustly recruited only to the homologous RSV budding sites. These data demonstrate that viral glycoproteins are not in preformed membrane patches prior to viral assembly but rather that glycoproteins are actively recruited to certain viral assembly sites.

scholarly journals As2O3 Enhances Retroviral Reverse Transcription and Counteracts Ref1 Antiviral Activity

2003 ◽  
Vol 77 (5) ◽  
pp. 3167-3180 ◽  
Author(s):  
Lionel Berthoux ◽  
Greg J. Towers ◽  
Cagan Gurer ◽  
Paolo Salomoni ◽  
Pier Paolo Pandolfi ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Leukemia Virus ◽  
Target Cells ◽  
Virion Assembly ◽  
Human T Cells ◽  
Pml Bodies ◽  
Steady State Levels ◽  
Nuclear Structures ◽  
Apoptosis Inducing Agents ◽  
Hiv 1

ABSTRACT Potent drugs such as cyclosporine have provided effective probes of signal transduction pathways and, as well, of human immunodeficiency virus type 1 (HIV-1) replication mechanisms. Recently, it was reported that As2O3, a drug used to treat acute promyelocytic leukemia (PML), stimulates HIV-1 replication. We found that As2O3 accelerates the kinetics of a spreading HIV-1 infection in human T cells and increases the number of cells bearing HIV-1 provirus after a single round of infection. The stimulatory effect occurred after membrane fusion and resulted in increased steady-state levels of newly synthesized viral cDNA. Stimulation was independent of HIV-1 env and most viral accessory genes, and As2O3 had no detectable effects on viral expression postintegration or virion assembly. Murine leukemia virus (MLV) transduction was enhanced by As2O3 to the same extent as HIV-1 transduction, but As2O3 had no additional effect on Fv1 restriction. In contrast, As2O3 largely overcame the specific block to N-tropic MLV reverse transcription posed by human Ref1. As2O3 disrupts PML bodies, nuclear structures named for a major component, the PML protein. We observed no changes in PML bodies in response to HIV-1 infection. Experiments with PML-null target cells indicated that PML has no effect on HIV-1 infectivity and is dispensable for the stimulatory effect of As2O3. As2O3 caused cell death in uninfected cells at the same concentrations which stimulate HIV-1 replication. Among four additional apoptosis-inducing agents, a boost in HIV-1 infectivity was observed only with carbonyl cyanide m-chlorophenylhydrazone, a compound which, like As2O3, disrupts the mitochondrial transmembrane potential. In summary, As2O3 stimulates retroviral reverse transcription, perhaps via effects on mitochondria, and provides a useful tool for characterizing Ref1.

scholarly journals Regulation of Human Immunodeficiency Virus Type 1 Env-Mediated Membrane Fusion by Viral Protease Activity

2004 ◽  
Vol 78 (2) ◽  
pp. 1026-1031 ◽  
Author(s):  
Tsutomu Murakami ◽  
Sherimay Ablan ◽  
Eric O. Freed ◽  
Yuetsu Tanaka
Keyword(s):  
Human Immunodeficiency Virus ◽  
Membrane Fusion ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytoplasmic Tail ◽  
Target Cells ◽  
Gag Protein ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We and others have presented evidence for a direct interaction between the matrix (MA) domain of the human immunodeficiency virus type 1 (HIV-1) Gag protein and the cytoplasmic tail of the transmembrane envelope (Env) glycoprotein gp41. In addition, it has been postulated that the MA domain of Gag undergoes a conformational change following Gag processing, and the cytoplasmic tail of gp41 has been shown to modulate Env-mediated membrane fusion activity. Together, these results raise the possibility that the interaction between the gp41 cytoplasmic tail and MA is regulated by protease (PR)-mediated Gag processing, perhaps affecting Env function. To examine whether Gag processing affects Env-mediated fusion, we compared the ability of wild-type (WT) HIV-1 Env and a mutant lacking the gp41 cytoplasmic tail to induce fusion in the context of an active (PR+) or inactive (PR−) viral PR. We observed that PR− virions bearing WT Env displayed defects in cell-cell fusion. Impaired fusion did not appear to be due to differences in the levels of virion-associated Env, in CD4-dependent binding to target cells, or in the formation of the CD4-induced gp41 six-helix bundle. Interestingly, truncation of the gp41 cytoplasmic tail reversed the fusion defect. These results suggest that interactions between unprocessed Gag and the gp41 cytoplasmic tail suppress fusion.

scholarly journals PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 77
Author(s):  
Yajing Fu ◽  
Sijia He ◽  
Abdul Waheed ◽  
Deemah Dabbagh ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Virus Particle ◽  
Influenza A ◽  
Leukemia Virus ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Immunodeficiency Virus ◽  
Vesicular Stomatitis ◽  
Selectin Binding ◽  
Anti Hiv ◽  
Hiv 1

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is primarily expressed on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits human immunodeficiency virus type 1 (HIV-1) replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here, we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein, vesicular stomatitis virus G glycoprotein, or lacking a viral glycoprotein, is impaired by PSGL-1. Mapping studies show that the extracellular, N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and the PSGL-1 cytoplasmic tail contributes to its inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or the expression of either Vpu or Nef, downregulates PSGL-1 from the cell surface; the expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a novel mechanism of action.

scholarly journals Solution Properties of Murine Leukemia Virus Gag Protein: Differences from HIV-1 Gag

2011 ◽  
Vol 85 (23) ◽  
pp. 12733-12741 ◽  
Author(s):  
S. A. K. Datta ◽  
X. Zuo ◽  
P. K. Clark ◽  
S. J. Campbell ◽  
Y.-X. Wang ◽  
...  
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Solution Properties ◽  
Gag Protein ◽  
Hiv 1 ◽  
Murine Leukemia

scholarly journals A Mutation in the Human Immunodeficiency Virus Type 1 Gag Protein Destabilizes the Interaction of the Envelope Protein Subunits gp120 and gp41

2006 ◽  
Vol 80 (5) ◽  
pp. 2405-2417 ◽  
Author(s):  
Melody R. Davis ◽  
Jiyang Jiang ◽  
Jing Zhou ◽  
Eric O. Freed ◽  
Christopher Aiken
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Protein ◽  
Cytoplasmic Tail ◽  
Target Cells ◽  
Gag Protein ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The Gag protein of human immunodeficiency virus type 1 (HIV-1) associates with the envelope protein complex during virus assembly. The available evidence indicates that this interaction involves recognition of the gp41 cytoplasmic tail (CT) by the matrix protein (MA) region of Pr55Gag. Here we show that substitution of Asp for Leu at position 49 (L49D) in MA results in a specific reduction in particle-associated gp120 without affecting the levels of gp41. Mutant virions were markedly reduced in single-cycle infectivity despite a relatively modest defect in fusion with target cells. Studies with HIV-1 particles containing decreased levels of envelope proteins suggested that the L49D mutation also inhibits a postentry step in infection. Truncation of the gp41 tail, or pseudotyping by vesicular stomatitis virus glycoprotein, restored both the fusion and infectivity of L49D mutant virions to wild-type levels. Truncation of gp41 also resulted in equivalent levels of gp120 on particles with and without the MA mutation and enhanced the replication of the L49D mutant virus in T cells. The impaired fusion and infectivity of L49D mutant particles were also complemented by a single point mutation in the gp41 CT that disrupted the tyrosine-containing endocytic motif. Our results suggest that an altered interaction between the MA domain of Gag and the gp41 cytoplasmic tail leads to dissociation of gp120 from gp41 during HIV-1 particle assembly, thus resulting in impaired fusion and infectivity.

scholarly journals Equine Infectious Anemia Virus Utilizes Host Vesicular Protein Sorting Machinery during Particle Release

2003 ◽  
Vol 77 (15) ◽  
pp. 8440-8447 ◽  
Author(s):  
Giancarlo O. Tanzi ◽  
Andrew J. Piefer ◽  
Paul Bates
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Leukemia Virus ◽  
Protein Sorting ◽  
Gag Protein ◽  
Particle Release ◽  
Late Domain ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Vacuolar Protein ◽  
Hiv 1

ABSTRACT A final step in retrovirus assembly, particle release from the cell, is modulated by a small motif in the Gag protein known as a late domain. Recently, human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus (M-MuLV) were shown to require components of the cellular vacuolar protein sorting (VPS) machinery for efficient viral release. HIV-1 interacts with the VPS pathway via an association of HIV-1 Gag with TSG101, a component of the cellular complexes involved in VPS. Equine infectious anemia virus (EIAV) is unique among enveloped viruses studied to date because it utilizes a novel motif, YPDL in Gag, as a late domain. Our analysis of EIAV assembly demonstrates that EIAV Gag release is blocked by inhibition of the VPS pathway. However, in contrast to HIV-1, EIAV Gag release is insensitive to TSG101 depletion and EIAV particles do not contain significant levels of TSG101. Finally, we demonstrate that fusing EIAV Gag directly with another cellular component of the VPS machinery, VPS28, can restore efficient release of an EIAV Gag late-domain mutant. These results provide evidence that retroviruses can interact with the cellular VPS machinery in several different ways to accomplish particle release.

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