scholarly journals Structure of Adeno-Associated Virus Type 4

2005 ◽  
Vol 79 (8) ◽  
pp. 5047-5058 ◽  
Author(s):  
Eric Padron ◽  
Valorie Bowman ◽  
Nikola Kaludov ◽  
Lakshmanan Govindasamy ◽  
Hazel Levy ◽  
...  
Keyword(s):  
Major Capsid Protein ◽  
Parvovirus B19 ◽  
Structural Similarity ◽  
Surface Topology ◽  
Target Cells ◽  
Adeno Associated Virus ◽  
Cryo Electron Microscopy ◽  
Specific Tissue ◽  
Surface Loops ◽  
Limited Sequence

ABSTRACT Adeno-associated virus (AAV) is a member of the Parvoviridae, belonging to the Dependovirus genus. Currently, several distinct isolates of AAV are in development for use in human gene therapy applications due to their ability to transduce different target cells. The need to manipulate AAV capsids for specific tissue delivery has generated interest in understanding their capsid structures. The structure of AAV type 4 (AAV4), one of the most antigenically distinct serotypes, was determined to 13-Å resolution by cryo-electron microscopy and image reconstruction. A pseudoatomic model was built for the AAV4 capsid by use of a structure-based sequence alignment of its major capsid protein, VP3, with that of AAV2, to which AAV4 is 58% identical and constrained by its reconstructed density envelope. The model showed variations in the surface loops that may account for the differences in receptor binding and antigenicity between AAV2 and AAV4. The AAV4 capsid surface topology also shows an unpredicted structural similarity to that of Aleutian mink disease virus and human parvovirus B19, autonomous members of the genus, despite limited sequence homology.

scholarly journals Completion of the AAV Structural Atlas: Serotype Capsid Structures Reveals Clade-Specific Features

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 101
Author(s):  
Mario Mietzsch ◽  
Ariana Jose ◽  
Paul Chipman ◽  
Nilakshee Bhattacharya ◽  
Nadia Daneshparvar ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Viral Proteins ◽  
Binding Pocket ◽  
Transduction Efficiency ◽  
Adeno Associated Virus ◽  
Cryo Electron Microscopy ◽  
Loop Conformations ◽  
Tissue Targeting ◽  
Clade C ◽  
Specific Tissue

The capsid structures of most Adeno-associated virus (AAV) serotypes, already assigned to an antigenic clade, have been previously determined. This study reports the remaining capsid structures of AAV7, AAV11, AAV12, and AAV13 determined by cryo-electron microscopy and three-dimensional image reconstruction to 2.96, 2.86, 2.54, and 2.76 Å resolution, respectively. These structures complete the structural atlas of the AAV serotype capsids. AAV7 represents the first clade D capsid structure; AAV11 and AAV12 are of a currently unassigned clade that would include AAV4; and AAV13 represents the first AAV2-AAV3 hybrid clade C capsid structure. These newly determined capsid structures all exhibit the AAV capsid features including 5-fold channels, 3-fold protrusions, 2-fold depressions, and a nucleotide binding pocket with an ordered nucleotide in genome-containing capsids. However, these structures have viral proteins that display clade-specific loop conformations. This structural characterization completes our three-dimensional library of the current AAV serotypes to provide an atlas of surface loop configurations compatible with capsid assembly and amenable for future vector engineering efforts. Derived vectors could improve gene delivery success with respect to specific tissue targeting, transduction efficiency, antigenicity or receptor retargeting.

scholarly journals Identification of a nonconventional motif necessary for the nuclear import of the human parvovirus B19 major capsid protein (VP2)

Virology ◽  
2003 ◽  
Vol 306 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Sylvie Pillet ◽  
Zeinab Annan ◽  
Serge Fichelson ◽  
F.rédéric Morinet
Keyword(s):  
Capsid Protein ◽  
Nuclear Import ◽  
Major Capsid Protein ◽  
Parvovirus B19 ◽  
Human Parvovirus B19

Structural Similarity between the Prion Domain of HET-s and a Homologue Can Explain Amyloid Cross-Seeding in Spite of Limited Sequence Identity

2010 ◽  
Vol 402 (2) ◽  
pp. 311-325 ◽  
Author(s):  
Christian Wasmer ◽  
Agnes Zimmer ◽  
Raimon Sabaté ◽  
Alice Soragni ◽  
Sven J. Saupe ◽  
...  
Keyword(s):  
Structural Similarity ◽  
Sequence Identity ◽  
Limited Sequence

scholarly journals Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 582 ◽  
Author(s):  
Sandra Skuja ◽  
Anda Vilmane ◽  
Simons Svirskis ◽  
Valerija Groma ◽  
Modra Murovska
Keyword(s):  
White Matter ◽  
Frontal Lobe ◽  
Brain Tissue ◽  
Morphological Changes ◽  
Structural Characteristics ◽  
Parvovirus B19 ◽  
Elderly Subjects ◽  
Target Cells ◽  
Human Parvovirus B19 ◽  
Pathogenic Potential

After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has been detected in the brain tissue by sequencing PCR products, little is known about its in vivo cell tropism and pathogenic potential in the CNS. To detect B19V and investigate the distribution of its target cells in the CNS, we studied brain autopsies of elderly subjects using molecular virology, and optical and electron microscopy methods. Our study detected B19V in brain tissue samples from both encephalopathy and control groups, suggesting virus persistence within the CNS throughout the host’s lifetime. It appears that within the CNS, the main target of B19V is oligodendrocytes. The greatest number of B19V-positive oligodendrocytes was found in the white matter of the frontal lobe. The number was significantly lower in the gray matter of the frontal lobe (p = 0.008) and the gray and white matter of the temporal lobes (p < 0.0001). The morphological changes observed in the encephalopathy group, propose a possible B19V involvement in the demyelination process.

scholarly journals Differential Activation of Innate Immune Responses by Adenovirus and Adeno-Associated Virus Vectors

2002 ◽  
Vol 76 (9) ◽  
pp. 4580-4590 ◽  
Author(s):  
Anne-Kathrin Zaiss ◽  
Qiang Liu ◽  
Gloria P. Bowen ◽  
Norman C. W. Wong ◽  
Jeffrey S. Bartlett ◽  
...  
Keyword(s):  
Immune System ◽  
Intravenous Administration ◽  
Innate Immune System ◽  
Innate Immune ◽  
Target Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Adeno Associated Virus ◽  
Tnf Α ◽  
Adenovirus Vectors

ABSTRACT Adenovirus vectors induce acute inflammation of infected tissues due to activation of the innate immune system and expression of numerous chemokines and cytokines in transduced target cells. In contrast, adeno-associated virus (AAV) vectors are not associated with significant inflammation experimentally or clinically. We tested the ability of AAV vectors to induce the expression of chemokines in vitro and to activate the innate immune system in vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the adenovirus vector AdlacZ induced the expression of multiple inflammatory chemokines including RANTES, interferon-inducible protein 10 (IP-10), interleukin-8 (IL-8), MIP-1β, and MIP-2 in a dose-dependent manner. The use of AAVlacZ did not induce the expression of these chemokines above baseline levels despite 40-fold-greater titers than AdlacZ and greater amounts of intracellular AAVlacZ genomes according to Southern and slot blot analysis. This finding confirmed that the lack of AAVlacZ induction of chemokine was not due to reduced transduction. In DBA/2 mice, the intravenous administration of 2.5 × 1011 particles of AAVlacZ resulted in the rapid induction of liver tumor necrosis factor alpha (TNF-α), RANTES, IP-10, MIP-1β, MCP-1, and MIP-2 mRNAs. However, 6 h following injection, chemokine mRNA levels returned to baseline. As expected, administration of 10-fold less AdlacZ caused an induction of liver TNF-α and chemokine mRNAs that persisted for more than 24 h posttransduction. Whereas intravenous administration of 2.5 × 1011 particles of AAVlacZ triggered a transient infiltration of neutrophils and CD11b+ cells into liver, this response stood in contrast to widespread inflammation and toxicity induced by AdlacZ. Kupffer cell depletion abolished AAVlacZ but not AdlacZ-induced chemokine expression and neutrophil infiltration. In summary, these results show that AAV vectors activate the innate immune system to a lesser extent than do adenovirus vectors and offer a possible explanation for the reduced inflammatory properties of AAV compared to adenovirus vectors.

scholarly journals Structural Characterization of Cuta- and Tusavirus: Insight into Protoparvoviruses Capsid Morphology

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 653
Author(s):  
Mario Mietzsch ◽  
Robert McKenna ◽  
Elina Väisänen ◽  
Jennifer C. Yu ◽  
Maria Ilyas ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Structure Evolution ◽  
Cellular Interactions ◽  
Human Pathogens ◽  
Cryo Electron Microscopy ◽  
Cellular Entry ◽  
Surface Loops ◽  
Antigenic Reactivity ◽  
Insight Into

Several members of the Protoparvovirus genus, capable of infecting humans, have been recently discovered, including cutavirus (CuV) and tusavirus (TuV). To begin the characterization of these viruses, we have used cryo-electron microscopy and image reconstruction to determine their capsid structures to ~2.9 Å resolution, and glycan array and cell-based assays to identify glycans utilized for cellular entry. Structural comparisons show that the CuV and TuV capsids share common features with other parvoviruses, including an eight-stranded anti-parallel β-barrel, depressions at the icosahedral 2-fold and surrounding the 5-fold axes, and a channel at the 5-fold axes. However, the viruses exhibit significant topological differences in their viral protein surface loops. These result in three separated 3-fold protrusions, similar to the bufaviruses also infecting humans, suggesting a host-driven structure evolution. The surface loops contain residues involved in receptor binding, cellular trafficking, and antigenic reactivity in other parvoviruses. In addition, terminal sialic acid was identified as the glycan potentially utilized by both CuV and TuV for cellular entry, with TuV showing additional recognition of poly-sialic acid and sialylated Lewis X (sLeXLeXLeX) motifs reported to be upregulated in neurotropic and cancer cells, respectively. These structures provide a platform for annotating the cellular interactions of these human pathogens.

scholarly journals Local Expression of Secondary Lymphoid Tissue Chemokine Delivered by Adeno-Associated Virus within the Tumor Bed Stimulates Strong Anti-Liver Tumor Immunity

2007 ◽  
Vol 81 (17) ◽  
pp. 9502-9511 ◽  
Author(s):  
Chun-min Liang ◽  
Cui-ping Zhong ◽  
Rui-xia Sun ◽  
Bin-bin Liu ◽  
Cheng Huang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymphoid Tissue ◽  
Critical Role ◽  
Antitumor Immune Response ◽  
Target Cells ◽  
Lymphoid Tissues ◽  
Adeno Associated Virus ◽  
Secondary Lymphoid Tissue ◽  
Local Expression

ABSTRACT Development of an effective antitumor immune response depends on the appropriate interaction of effector and target cells. Thus, the expression of chemokines within the tumor may induce a more potent antitumor immune response. Secondary lymphoid tissue chemokine (SLC) is known to play a critical role in establishing a functional microenvironment in secondary lymphoid tissues. Its capacity to attract dendritic cells (DCs) and colocalize them with T cells makes it a good therapeutic candidate against cancer. In this study, we used SLC as a treatment for tumors established from a murine hepatocellular carcinoma model. SLC was encoded by recombinant adeno-associated virus (rAAV), a system chosen for the low host immunity and high efficiency of transduction, enabling long-term expression of the gene of interest. As a result, rAAV-SLC induced a significant delay of tumor progression, which was paralleled by a profound infiltration of DCs and activated CD4+ T cells and CD8+ T cells (CD3+ CD69+ cells) into the tumor site. In addition, rAAV-SLC treatment was also found to reduce tumor growth in nude mice, most likely due to inhibition of neoangiogenesis. In conclusion, local expression of SLC by rAAV represents a promising approach to induce immune-mediated regression of malignant tumors.

scholarly journals Filling Adeno-Associated Virus Capsids: Estimating Success by Cryo-Electron Microscopy

2019 ◽  
Vol 30 (12) ◽  
pp. 1449-1460
Author(s):  
Suriyasri Subramanian ◽  
Anna C. Maurer ◽  
Carol M. Bator ◽  
Alexander M. Makhov ◽  
James F. Conway ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Adeno Associated Virus ◽  
Cryo Electron Microscopy ◽  
Virus Capsids

scholarly journals The leukotriene B4receptor functions as a novel type of coreceptor mediating entry of primary HIV-1 isolates into CD4-positive cells

1998 ◽  
Vol 95 (16) ◽  
pp. 9530-9534 ◽  
Author(s):  
Christer Owman ◽  
Alfredo Garzino-Demo ◽  
Fiorenza Cocchi ◽  
Mikulas Popovic ◽  
Alan Sabirsh ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Viral Entry ◽  
Chemokine Receptors ◽  
Structural Similarity ◽  
Target Cells ◽  
Natural Ligand ◽  
Hiv 1 ◽  
Entry Efficiency ◽  
Receptor Family

The recently cloned human chemoattractant receptor-like (CMKRL)1, which is expressedin vivoin CD4-positive immune cells, has structural homology with the two chemokine receptors C-C chemokine receptor (CCR)5 and C-X-C chemokine receptor (CXCR)4, which serve as the major coreceptors necessary for fusion of the HIV-1 envelope with target cells. In view of the structural similarity, CMKRL1 was tested for its possible function as another HIV-1 coreceptor after stable expression in murine fibroblasts bearing the human CD4 receptor. The cells were infected with 10 primary clinical isolates of HIV-1, and entry was monitored by semiquantitative PCR of viral DNA. The efficiency of the entry was compared with the entry taking place in CD4-positive cells expressing either CCR5 or CXCR4. Seven of the isolates used CMKRL1 for viral entry; they were mainly of the syncytium-inducing phenotype and also used CXCR4. Entry efficiency was higher with CMKRL1 than with CXCR4 for more than half of these isolates. Three of the ten isolates did not use CMKRL1; instead, entry was mediated by both CCR5 and CXCR4. The experiments thus indicate that CMKRL1 functions as a coreceptor for the entry of HIV-1 into CD4-positive cells. In the course of this study, leukotriene B4was shown to be the natural ligand for this receptor (now designated BLTR), which therefore represents a novel type of HIV-1 coreceptor along with the previously identified chemokine receptors. BLTR belongs to the same general chemoattractant receptor family as the chemokine receptors but is structurally more distant from them than are any of the previously described HIV-1 coreceptors.

Nanotechnology for Gene Delivery to the Eye

2009 ◽  
Vol 03 (01) ◽  
pp. 7 ◽  
Author(s):  
Swita R Singh ◽  
Uday B Kompella ◽  
◽  
Keyword(s):  
Gene Delivery ◽  
Enzymatic Degradation ◽  
Viral Vectors ◽  
Viral Vector ◽  
Target Cells ◽  
Loading Capacity ◽  
Adeno Associated Virus ◽  
Complementary Dna ◽  
Privileged Status ◽  
Potential Applications

The relatively immune-privileged status of the eye makes it an interesting target for gene delivery. Gene delivery to the eye using viral vectors via subretinal and intravitreal injections has been extensively investigated. Recently, the safety of recombinant adeno-associated virus vector expressing RPE65 complementary DNA (cDNA) in a limited clinical trial of three patients has also been reported. Nanotechnology-based non-viral vectors offer the advantages of safety and flexibility in terms of loading capacity and delivery system design compared with viral vectors. An ideal non-viral vector should be non-toxic, efficiently taken up into the target cells and conducive to gene expression, and should protect the gene against enzymatic degradation. Multiple kinds of nanotechnology-based non-viral vectors have been investigated for potential applications for gene delivery to the eye, namely nanoplexes, dendrimers, micelles, nanoparticles and liposomes. This article summarises and discusses key advances in the application of nanotechnology for gene delivery to the eye.

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