Advancing Research of Anelloviruses

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 7595

Special Issue Editors


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Guest Editor
1. Department of Medicine and Surgery, University of Insubria, Varese, Italy
2. Laboratory of Virology, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
Interests: anelloviruses; virome; SARS-CoV-2; HCV
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Guest Editor
Department of Translational Research, University of Pisa, 56100 Pisa, Italy
Interests: anelloviruses; virome; SARS-CoV-2; next-generation sequencing

Special Issue Information

Dear Colleagues,

Anelloviruses (AV) are a vast group of agents discovered in recent years that may infect humans and various animal species. The first indication of their existence was in 1997, when Japanese scientists, using representational difference analysis for examining the blood of patients with cryptogenetic post-transfusion hepatitis, detected a novel virus with a particularly small genome formed by a circular single-stranded DNA of negative polarity. This new virus was named TT virus (TTV) after the initials of the first patient in whom it was identified, but its extended name was changed in 2004 to Torquetenovirus (from the Latin words torques and tenuis, meaning necklace and thin, respectively) to maintain the original acronym and conform to the International Committee on Taxonomy of Viruses rule that no official virus designation should be derived from people’s names. The discovery of TTV soon opened a Pandora’s box of new viruses. In fact, it was followed, in the year 2000 by the detection in diseased and healthy individuals of numerous related, previously unrecognized viruses with genome properties clearly similar to those of TTV, although often very genetically divergent from it. Furthermore, PCR testing of some blood donors for TTV produced shorter amplicons than expected if the virus amplified was truly TTV, and further characterization revealed the existence of additional viruses also clearly related to TTV but with a smaller genome, namely Torquetenominivirus (TTMV) and Torquetenomidivirus (TTMVD). Since 2009, all these viruses have been classified in the newly established family Anelloviridae (from anellus, Latin for "ring," to indicate the circular genome).

Despite the rapid accumulation of knowledge on TTV and related AV, many fundamental aspects of their infection remain unresolved. Although AV have been discovered to be extremely common, with abundant viral DNA detectable in the plasma of 80% or more of the general population worldwide, their significance for human health remains unknown. It has been proposed that AV should be considered completely nonpathogenic, and the recent evidence that they represent the most abundant members of the human virome speaks in favor of this hypothesis. However, at this time, it seems wiser to consider AV an "orphan of disease", similar to what has previously been done for many other viruses that, many years after their discovery, were found to produce significant pathologies.

Dr. Fabrizio Maggi
Dr. Pietro Giorgio Spezia
Guest Editors

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Keywords

  • TTV
  • TTMV
  • TTMDV
  • virome
  • viral species
  • immune system
  • orphan virus

Published Papers (8 papers)

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Research

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10 pages, 712 KiB  
Article
Long-Read Nanopore-Based Sequencing of Anelloviruses
by Raghavendran Anantharam, Dylan Duchen, Andrea L. Cox, Winston Timp, David L. Thomas, Steven J. Clipman and Abraham J. Kandathil
Viruses 2024, 16(5), 723; https://doi.org/10.3390/v16050723 - 02 May 2024
Viewed by 322
Abstract
Routinely used metagenomic next-generation sequencing (mNGS) techniques often fail to detect low-level viremia (<104 copies/mL) and appear biased towards viruses with linear genomes. These limitations hinder the capacity to comprehensively characterize viral infections, such as those attributed to the Anelloviridae family. These [...] Read more.
Routinely used metagenomic next-generation sequencing (mNGS) techniques often fail to detect low-level viremia (<104 copies/mL) and appear biased towards viruses with linear genomes. These limitations hinder the capacity to comprehensively characterize viral infections, such as those attributed to the Anelloviridae family. These near ubiquitous non-pathogenic components of the human virome have circular single-stranded DNA genomes that vary in size from 2.0 to 3.9 kb and exhibit high genetic diversity. Hence, species identification using short reads can be challenging. Here, we introduce a rolling circle amplification (RCA)-based metagenomic sequencing protocol tailored for circular single-stranded DNA genomes, utilizing the long-read Oxford Nanopore platform. The approach was assessed by sequencing anelloviruses in plasma drawn from people who inject drugs (PWID) in two geographically distinct cohorts. We detail the methodological adjustments implemented to overcome difficulties inherent in sequencing circular genomes and describe a computational pipeline focused on anellovirus detection. We assessed our protocol across various sample dilutions and successfully differentiated anellovirus sequences in conditions simulating mixed infections. This method provides a robust framework for the comprehensive characterization of circular viruses within the human virome using the Oxford Nanopore. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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14 pages, 839 KiB  
Article
Torque Teno Virus (TTV) in Renal Transplant Recipients: Species Diversity and Variability
by Noelia Soledad Reyes, Pietro Giorgio Spezia, Raquel Jara, Fabio Filippini, Natalia Boccia, Gonzalo García, Eliana Hermida, Fernando Adrian Poletta, Mauro Pistello, Gustavo Laham, Fabrizio Maggi and Marcela Echavarria
Viruses 2024, 16(3), 432; https://doi.org/10.3390/v16030432 - 11 Mar 2024
Viewed by 747
Abstract
Torque Teno Virus (TTV) is a nonpathogenic and ubiquitous ssDNA virus, a member of the Anelloviridae family. TTV has been postulated as a biomarker in transplant patients. This study aimed to determine the TTV species diversity and variability in renal transplant recipients and [...] Read more.
Torque Teno Virus (TTV) is a nonpathogenic and ubiquitous ssDNA virus, a member of the Anelloviridae family. TTV has been postulated as a biomarker in transplant patients. This study aimed to determine the TTV species diversity and variability in renal transplant recipients and to associate species diversity with the corresponding TTV viral load. From 27 recipients, 30 plasma samples were selected. Viral load was determined using two real-time PCR assays, followed by RCA-NGS and ORF1 phylogenetic analysis. The TTV diversity was determined in all samples. Variability was determined in three patients with two sequential samples (pre- and post-transplantation). Most of the samples presented multiple TTV species, up to 15 different species were detected. In the pre-transplant samples (n = 12), the most prevalent species were TTV3 (75%) and TTV13 (75%), and the median number of species per sample was 5 (IQR: 4–7.5). TTV3 was also the most prevalent (56%) in the post-transplant samples (n = 18), and the median number of species was 2 (IQR: 1.8–5.5). No significant correlation between the number of species and viral load was found. The number and type of TTV species showed total variability over time. We report high TTV species diversity in Argentinian recipients, especially in pre-transplant period, with total intra-host variability. However, we found no significant correlation between this high diversity and TTV viral load. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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13 pages, 848 KiB  
Article
High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients
by Jip Jonker, Caecilia S. E. Doorenbos, Daan Kremer, Edmund J. Gore, Hubert G. M. Niesters, Coretta van Leer-Buter, Philippe Bourgeois, Margery A. Connelly, Robin P. F. Dullaart, Stefan P. Berger, Jan-Stephan F. Sanders and Stephan J. L. Bakker
Viruses 2024, 16(1), 143; https://doi.org/10.3390/v16010143 - 18 Jan 2024
Viewed by 959
Abstract
Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ [...] Read more.
Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ transplant recipients. Additionally, there is a growing interest in the role of HDL particles in immune function; therefore, assessment of both HDL concentrations and TTV load may be of interest in transplant recipients. The objective of this study was to analyze TTV loads and HDL parameters in serum samples collected at least one year post-transplantation from 656 stable outpatient kidney transplant recipients (KTRs), enrolled in the TransplantLines Food and Nutrition Cohort (Groningen, the Netherlands). Plasma HDL particles and subfractions were measured using nuclear magnetic resonance spectroscopy. Serum TTV load was measured using a quantitative real-time polymerase chain reaction. Associations between HDL parameters and TTV load were examined using univariable and multivariable linear regression. The median age was 54.6 [IQR: 44.6 to 63.1] years, 43.3% were female, the mean eGFR was 52.5 (±20.6) mL/min/1.73 m2 and the median allograft vintage was 5.4 [IQR: 2.0 to 12.0] years. A total of 539 participants (82.2%) had a detectable TTV load with a mean TTV load of 3.04 (±1.53) log10 copies/mL, the mean total HDL particle concentration was 19.7 (±3.4) μmol/L, and the mean HDL size was 9.1 (±0.5) nm. The univariable linear regression revealed a negative association between total HDL particle concentration and TTV load (st.β = −0.17, 95% CI st.β: −0.26 to −0.09, p < 0.001). An effect modification of smoking behavior influencing the association between HDL particle concentration and TTV load was observed (Pinteraction = 0.024). After adjustment for age, sex, alcohol intake, hemoglobin, eGFR, donor age, allograft vintage and the use of calcineurin inhibitors, the negative association between HDL particle concentration and TTV load remained statistically significant in the non-smoking population (st.β = −0.14, 95% CI st.β: −0.23 to −0.04, p = 0.006). Furthermore, an association between small HDL particle concentration and TTV load was found (st.β = −0.12, 95% CI st.β: −0.22 to −0.02, p = 0.017). Higher HDL particle concentrations were associated with a lower TTV load in kidney transplant recipients, potentially indicative of a higher immune function. Interventional studies are needed to provide causal evidence on the effects of HDL on the immune system. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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14 pages, 2041 KiB  
Article
The Impact of First-Time SARS-CoV-2 Infection on Human Anelloviruses
by Anne L. Timmerman, Lisanne Commandeur, Martin Deijs, Maarten G. J. M. Burggraaff, A. H. Ayesha Lavell, Karlijn van der Straten, Khadija Tejjani, Jacqueline van Rijswijk, Marit J. van Gils, Jonne J. Sikkens, Marije K. Bomers and Lia van der Hoek
Viruses 2024, 16(1), 99; https://doi.org/10.3390/v16010099 - 09 Jan 2024
Viewed by 1052
Abstract
Members of the Anelloviridae family dominate the blood virome, emerging early in life. The anellome, representing the variety of anelloviruses within an individual, stabilizes by adulthood. Despite their supposedly commensal nature, elevated anellovirus concentrations under immunosuppressive treatment indicate an equilibrium controlled by immunity. [...] Read more.
Members of the Anelloviridae family dominate the blood virome, emerging early in life. The anellome, representing the variety of anelloviruses within an individual, stabilizes by adulthood. Despite their supposedly commensal nature, elevated anellovirus concentrations under immunosuppressive treatment indicate an equilibrium controlled by immunity. Here, we investigated whether anelloviruses are sensitive to the immune activation that accompanies a secondary infection. As a model, we investigated 19 health care workers (HCWs) with initial SARS-CoV-2 infection, with blood sampling performed pre and post infection every 4 weeks in a 3-month-follow-up during the early 2020 COVID-19 pandemic. A concurrently followed control group (n = 27) remained SARS-CoV-2-negative. Serum anellovirus loads were measured using qPCR. A significant decrease in anellovirus load was found in the first weeks after SARS-CoV-2 infection, whereas anellovirus concentrations remained stable in the uninfected control group. A restored anellovirus load was seen approximately 10 weeks after SARS-CoV-2 infection. For five subjects, an in-time anellome analysis via Illumina sequencing could be performed. In three of the five HCWs, the anellome visibly changed during SARS-CoV-2 infection and returned to baseline in two of these cases. In conclusion, anellovirus loads in blood can temporarily decrease upon an acute secondary infection. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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14 pages, 2565 KiB  
Article
Smoking, Alcohol Intake and Torque Teno Virus in Stable Kidney Transplant Recipients
by Caecilia S. E. Doorenbos, Jip Jonker, Jiasi Hao, Edmund J. Gore, Daan Kremer, Tim J. Knobbe, Anoek A. E. de Joode, Jan Stephan F. Sanders, Olivier Thaunat, Hubert G. M. Niesters, Coretta C. Van Leer-Buter and Stephan J. L. Bakker
Viruses 2023, 15(12), 2387; https://doi.org/10.3390/v15122387 - 06 Dec 2023
Cited by 1 | Viewed by 1037
Abstract
Torque Teno Virus (TTV) is a non-pathogenic virus that is highly prevalent among kidney transplant recipients (KTRs). Its circulating load is associated with an immunological status in KTR and is considered a promising tool for guiding immunosuppression. To allow for optimal guidance, it [...] Read more.
Torque Teno Virus (TTV) is a non-pathogenic virus that is highly prevalent among kidney transplant recipients (KTRs). Its circulating load is associated with an immunological status in KTR and is considered a promising tool for guiding immunosuppression. To allow for optimal guidance, it is important to identify other determinants of TTV load. We aimed to investigate the potential association of smoking and alcohol intake with TTV load. For this cross-sectional study, serum TTV load was measured using PCR in stable kidney transplant recipients at ≥1 year after transplantation, and smoking status and alcohol intake were assessed through questionnaires and measurements of urinary cotinine and ethyl glucuronide. A total of 666 KTRs were included (57% male). A total of 549 KTR (82%) had a detectable TTV load (3.1 ± 1.5 log10 copies/mL). In KTR with a detectable TTV load, cyclosporin and tacrolimus use were positively associated with TTV load (St. β = 0.46, p < 0.001 and St. β = 0.66, p < 0.001, respectively), independently of adjustment for potential confounders. Current smoking and alcohol intake of >20 g/day were negatively associated with TTV load (St. β = −0.40, p = 0.004 and St. β = −0.33, p = 0.009, respectively), independently of each other and of adjustment for age, sex, kidney function, time since transplantation and calcineurin inhibitor use. This strong association of smoking and alcohol intake with TTV suggests a need to account for the smoking status and alcohol intake when applying TTV guided immunosuppression in KTR. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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11 pages, 2100 KiB  
Article
Kinetics of TTV Loads in Peripheral Blood Mononuclear Cells of Early Treated Acute HIV Infections
by Isabella Abbate, Gabriella Rozera, Eleonora Cimini, Fabrizio Carletti, Eleonora Tartaglia, Marika Rubino, Silvia Pittalis, Rozenn Esvan, Roberta Gagliardini, Annalisa Mondi, Valentina Mazzotta, Marta Camici, Enrico Girardi, Francesco Vaia, Vincenzo Puro, Andrea Antinori and Fabrizio Maggi
Viruses 2023, 15(9), 1931; https://doi.org/10.3390/v15091931 - 15 Sep 2023
Viewed by 821
Abstract
Torquetenovirus (TTV) is the most abundant component of the human blood virome and its replication is controlled by a functioning immune system. In this study, TTV replication was evaluated in 21 people with acute HIV infection (AHI) and immune reconstitution following antiretroviral therapy [...] Read more.
Torquetenovirus (TTV) is the most abundant component of the human blood virome and its replication is controlled by a functioning immune system. In this study, TTV replication was evaluated in 21 people with acute HIV infection (AHI) and immune reconstitution following antiretroviral therapy (ART). PBMC-associated TTV and HIV-1 DNA, as well as plasma HIV-1 RNA, were measured by real-time PCR. CD4 and CD8 differentiation, activation, exhaustion, and senescence phenotypes were analyzed by flow cytometry. Thirteen healthy donors (HD) and twenty-eight chronically infected HIV individuals (CHI), late presenters at diagnosis, were included as control groups. TTV replication in AHI seems to be controlled by the immune system being higher than in HD and lower than in CHI. During ART, a transient increase in TTV DNA levels was associated with a significant perturbation of activation and senescence markers on CD8 T cells. TTV loads were positively correlated with the expansion of CD8 effector memory and CD57+ cells. Our results shed light on the kinetics of TTV replication in the context of HIV acute infection and confirm that the virus replication is strongly regulated by the modulation of the immune system. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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6 pages, 567 KiB  
Communication
SCANellome: Analysis of the Genomic Diversity of Human and Non-Human Primate Anelloviruses from Metagenomics Data
by Florian Laubscher, Laurent Kaiser and Samuel Cordey
Viruses 2023, 15(7), 1575; https://doi.org/10.3390/v15071575 - 19 Jul 2023
Cited by 1 | Viewed by 1134
Abstract
Anelloviruses are extremely prevalent in the human population and are considered to be commensal parts of the human virome. The best-known member in humans is the Torque teno virus. Recent metagenomic next-generation sequencing investigations have helped reveal the considerable number of species and [...] Read more.
Anelloviruses are extremely prevalent in the human population and are considered to be commensal parts of the human virome. The best-known member in humans is the Torque teno virus. Recent metagenomic next-generation sequencing investigations have helped reveal the considerable number of species and genotypes from the same genus that can be co-detected within a single individual and that this diversity increases as a function of age during the first months/years of life. As a result, to date, the bioinformatics analysis of this genetic diversity remains complex and constraining for researchers. Here, we present SCANellome, a user-friendly tool to investigate the anellome composition at the genus, species, and genotype levels of samples from metagenomics data generated by the Illumina and Nanopore platforms. SCANellome is based on an in-house up-to-date database that includes all human and non-human primate anellovirus reference sequences available on GenBank and meets the latest classification criteria established by the International Committee on Taxonomy of Viruses. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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Review

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0 pages, 600 KiB  
Review
Torque Teno Virus DNA Load in Blood as an Immune Status Biomarker in Adult Hematological Patients: The State of the Art and Future Prospects
by Eliseo Albert, Estela Giménez, Rafael Hernani, José Luis Piñana, Carlos Solano and David Navarro
Viruses 2024, 16(3), 459; https://doi.org/10.3390/v16030459 - 17 Mar 2024
Viewed by 781
Abstract
A solid body of scientific evidence supports the assumption that Torque teno virus (TTV) DNA load in the blood compartment may behave as a biomarker of immunosuppression in solid organ transplant recipients; in this clinical setting, high or increasing TTV DNA levels precede [...] Read more.
A solid body of scientific evidence supports the assumption that Torque teno virus (TTV) DNA load in the blood compartment may behave as a biomarker of immunosuppression in solid organ transplant recipients; in this clinical setting, high or increasing TTV DNA levels precede the occurrence of infectious complications, whereas the opposite anticipates the development of acute rejection. The potential clinical value of the TTV DNA load in blood to infer the risk of opportunistic viral infection or immune-related (i.e., graft vs. host disease) clinical events in the hematological patient, if any, remains to be determined. In fact, contradictory data have been published on this matter in the allo-SCT setting. Studies addressing this topic, which we review and discuss herein, are highly heterogeneous as regards design, patient characteristics, time points selected for TTV DNA load monitoring, and PCR assays used for TTV DNA quantification. Moreover, clinical outcomes are often poorly defined. Prospective, ideally multicenter, and sufficiently powered studies with well-defined clinical outcomes are warranted to elucidate whether TTV DNA load monitoring in blood may be of any clinical value in the management of hematological patients. Full article
(This article belongs to the Special Issue Advancing Research of Anelloviruses)
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