Comprehensive profiling of antibody responses to the human anellome using programmable phage display

Venkataraman, Thiagarajan; Swaminathan, Harish; Arze, Cesar; Jacobo, Sarah M; Bhattacharyya, Agamoni; David, Tyler; Nawandar, Dhananjay M.; Delagrave, Simon; Mani, Vinidhra; Yozwiak, Nathan L.; Larman, H. Benjamin

doi:10.1016/j.celrep.2022.111754

Cited by 14 publications

(16 citation statements)

References 39 publications

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“…Given the reports of AAV9 and other AAV serotype-induced CNS toxicity [Hordeaux 2020, Van Alstyne 2021, Suriano 2021, Guo 2023], the data reported here, though preliminary, suggest that ANV.eGFP may result in less axon degeneration compared to AAV9.eGFP. Anelloviruses have been described as weakly immunogenic and non-pathogenic [Venkataraman 2022, Liou 2022, Kaczorowska 2023, Timmerman 2024]. It will be of great interest to further investigate the comparison between AAV9 and Anellovector-mediated transgene expression in a neuronal system to determine if Anellovector-mediated transgene expression is better tolerated by the host.…”

Section: Discussionmentioning

confidence: 99%

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

Prince,

Bounoutas,

Zhou

et al. 2024

Preprint

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Anelloviridae is a family of non-enveloped viruses with negative-sense, circular, single-stranded deoxyribonucleic acid (ssDNA) genomes that infect vertebrates and are a ubiquitous component of the human virome. Human anelloviruses evade induction of humoral immune responses and appear to be non-pathogenic. These properties, in conjunction with their enormous genomic diversity and wide tissue distribution, make anelloviruses compelling candidates as vectors for next-generation genetic medicines. Here we report the first gene delivery vector system based on a human commensal virus. This Anellovector is based on a virus of the Betatorquevirus genus. Production is enabled by the development of the Self-Amplifying Trans-complementation of a Universal Recombinant aNellovector (SATURN) system, which relies on a self-replicating plasmid to provide viral proteins in trans that drive replication and capsid-dependent packaging of vector genomes. The SATURN system also utilizes a Cre-lox-based recombination mechanism to generate single unit-sized circular genomes inside the MOLT-4 production cell line. We demonstrate that the SATURN system can package a vector genome from a single betatorquevirus with capsids from multiple betatorquevirus species, supporting the feasibility of establishing a novel vector platform that takes advantage of the remarkable diversity of anelloviruses. The Anellovector demonstrated function in vitro in retinal pigment epithelial (RPE) cells. The Anellovector also demonstrated durable in vivo function in the mouse eye for 9 months after subretinal administration, and achieved comparable gene expression to dose-matched adeno-associated virus 9 (AAV9) when transduced by the intracerebroventricular (ICV) route of administration. To our knowledge, this is the first report of a functional anellovirus-based gene therapy vector. Anellovectors have great potential to deliver safe, redosable, and potent therapeutics, helping to expand the reach of programmable medicines.

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Section: Discussionmentioning

confidence: 99%

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

Prince,

Bounoutas,

Zhou

et al. 2024

Preprint

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“…ORF1 protein elicits immune responses ( Kakkola, Bondén, and Hedman et al. 2008 ) although they may not be very strong, especially in the case of alphatorqueviruses ( Venkataraman, Swaminathan, and Arze et al. 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…2022 ). The most immunogenic region is located at the C-terminal of the ORF1 protein, and HVR was reported to elicit weaker responses ( Venkataraman, Swaminathan, and Arze et al. 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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Anellovirus evolution during long-term chronic infection

et al. 2023

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Human anelloviruses (AVs) are extremely genetically diverse, widespread in the human population, and cause chronic infections. However, the evolutionary dynamics of AVs within single hosts is currently unknown, and it is unclear whether these changes have an implication on the long-term persistence of AVs in the host. Here, we assessed the evolutionary dynamics of six AV lineages during 30 years of chronic infection at single host resolution. The total number of substitutions and the number of variable sites increased over time. However, not all substitutions reached population fixation, showing that AV lineages form heterogeneous swarms within the host. Most substitutions occurred within a hypervariable region (HVR) located between nucleotide positions 800 and 1300 of ORF1, which is known to be located within the spike domain. Different regions of the ORF1 gene undergo either positive or negative selection pressure. Sites under strong diversifying selection pressure were detected in the HVR, while the majority of the sites under purifying selection were detected outside this region. The HVR may play the role of an immunological decoy that prevents antibodies from binding to more vulnerable parts of ORF1. Moreover, the frequent substitutions in this region may increase the chances of AV particles escaping immune recognition.

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“…As antibody-mediated neutralization of a virus depends on the epitopes being targeted, unveiling the locations where antibodies bind is of interest. In 2022, Venkataraman et al ( 2022 ) used AnelloScan, a phage immunoprecipitation-sequencing assay (PhIp-Seq) to analyze the binding ability and affinity of antibodies to TTV, as well as TTMV- and TTMDV-derived linear peptides from ORF1, ORF2 ORF3, and TAIP (Venkataraman et al 2022 ). The assay was not limited to a single genotype of each genus, as no less than 800 different human anelloviruses isolates (326 TTVs, 357 TTMVs, and 146 TTMDVs) were tested in the AnelloScan.…”

Section: The Adaptive Immune Responsementioning

confidence: 99%

Anelloviruses versus human immunity: how do we control these viruses?

Timmerman,

Schönert,

van der Hoek

2024

FEMS Microbiology Reviews

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One continuous companion and one of the major players in the human blood virome are members of the Anelloviridae family. Anelloviruses are probably found in all humans, infection occurs early in life and the composition (anellome) is thought to remain stable and personal during adulthood. The stable anellome implies a great balance between the host immune system and the virus. However, the lack of a robust culturing system hampers direct investigation of interactions between virus and host cells. Other techniques however, including next generation sequencing, AnelloScan-antibody tests, evolution selection pressure analysis and virus protein structures, do provide new insights into the interactions between anelloviruses and the host immune system. This review aims at providing an overview of the current knowledge on the immune mechanisms acting on anelloviruses and the countering viral mechanisms allowing immune evasion.

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Comprehensive profiling of antibody responses to the human anellome using programmable phage display

Cited by 14 publications

References 39 publications

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

Anellovirus evolution during long-term chronic infection

Anelloviruses versus human immunity: how do we control these viruses?

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