Anelloviridae in the Human Virome
Overview
Anelloviridae is a family of small, non-enveloped viruses with circular, single-stranded DNA genomes that are ubiquitous in the human population. The most well-studied members of this family are Torque teno viruses (TTV), which were first discovered in 1997 in a Japanese patient with post-transfusion hepatitis of unknown etiology. Since then, numerous related viruses have been identified and classified within the Anelloviridae family, including Torque teno mini virus (TTMV) and Torque teno midi virus (TTMDV).
Anelloviruses are remarkably prevalent, with studies indicating that 80-90% of the adult human population worldwide carries TTV in their blood, regardless of age, socioeconomic status, or health condition. Despite this high prevalence, anelloviruses have not been definitively linked to any specific disease, earning them the status of "orphan viruses." However, emerging research suggests they may play indirect roles in various health conditions and serve as potential biomarkers for immune system status.
The Anelloviridae family comprises 30 different genera and 156 species, with three genera known to infect humans: Alphatorquevirus (including TTV), Betatorquevirus (including TTMV), and Gammatorquevirus (including TTMDV). These viruses collectively form what is known as the human "anellome," representing a significant component of the human virome.
Characteristics
Anelloviruses possess several distinctive characteristics:
Genome Structure: They have circular, negative-sense, single-stranded DNA genomes that vary in size between genera: TTV (3.5-3.9 kb), TTMDV (up to 2.3 kb), and TTMV (2.7-2.9 kb). The genome contains at least four open reading frames (ORFs), with ORF1 having a hypervariable region.
Morphology: Anelloviruses are non-enveloped viruses with icosahedral symmetry. Their capsids consist of 12 pentameric capsomers with T=1 icosahedral symmetry, and their virions are spherical with a diameter of approximately 30-50 nm.
Genetic Diversity: Anelloviruses exhibit extreme genetic diversity, comparable to that found in RNA viruses. The untranslated region (UTR) of the genome is well conserved, while the translated regions show high variability. This diversity allows for the simultaneous infection of a single individual with multiple strains and species.
Replication: Anelloviruses replicate in the cell nucleus using a circular replication mechanism. They likely utilize cellular polymerases for genome replication, as they do not encode their own DNA polymerase. T lymphocytes have been identified as the principal site for their multiplication, though they can replicate in various tissues.
Tissue Tropism: Anelloviruses demonstrate broad tissue tropism and have been detected in numerous tissues and body fluids, including blood, saliva, urine, feces, sweat, semen, breast milk, bile, liver, bone marrow, brain, and cervical samples.
Role in Human Microbiome
Anelloviruses are integral components of the human virome, representing approximately 70% of the total blood virome. Their role in the human microbiome is characterized by several key aspects:
Establishment and Persistence
Anelloviruses are acquired very early in life through multiple routes, including placental transmission, respiratory routes, and blood transfusions. Studies have detected TTV in cord blood and amniotic fluid, suggesting vertical transmission from mother to fetus. After initial infection, anelloviruses establish lifelong persistence in the host, with viral loads varying between individuals and over time within the same individual.
Distribution Across Body Sites
While anelloviruses are most commonly studied in blood, they have been detected in virtually all human tissues and body fluids. In the blood, they primarily infect T lymphocytes but can also be found in other cell types. Their presence in saliva, respiratory secretions, and fecal samples suggests they are part of the normal microbiome of multiple body sites.
Interaction with Host Immune System
Anelloviruses have evolved sophisticated mechanisms to evade the host immune system, allowing for their persistent infection. They can encode microRNAs (miRNAs) that may modulate host immune responses and regulate viral reactivation. The viral load of anelloviruses, particularly TTV, has been observed to fluctuate in response to changes in the host's immune status, increasing during periods of immunosuppression and decreasing when immune function is restored.
Health Implications
Despite their high prevalence, the direct health implications of anelloviruses remain largely unclear. However, several potential roles in human health and disease have been proposed:
Potential Role in Cancer: Some studies have suggested associations between anelloviruses and various cancers, including hepatocellular carcinoma, gastric cancer, and lung cancer. These associations may involve indirect mechanisms, such as the modulation of the host immune response or interactions with other oncogenic viruses.
Immune System Diseases: Anelloviruses have been linked to various immune system disorders, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The viral load of TTV has been found to be higher in patients with these conditions, suggesting a potential role in disease pathogenesis or as a consequence of immune dysregulation.
Viral Coinfections: Anelloviruses may interact with other viral infections, potentially influencing their course and severity. Studies have reported associations between anelloviruses and infections with hepatitis viruses, HIV, and other pathogens. These interactions may involve competition for cellular resources, modulation of immune responses, or direct viral interference.
Biomarker for Immune Status: One of the most promising applications of anelloviruses is their potential use as biomarkers for immune system status. TTV viral load has been shown to increase during periods of immunosuppression and decrease when immune function is restored, making it a potential indicator of immune competence in various clinical settings.
Metabolic Activities
The metabolic activities of anelloviruses within the human host are not fully understood, primarily due to the lack of efficient cell culture systems and animal models. However, several aspects of their interaction with host metabolism have been identified:
MicroRNA Production: Anelloviruses, particularly TTV, can encode microRNAs that may regulate both viral and host gene expression. These miRNAs could potentially influence various cellular metabolic pathways and contribute to viral persistence.
Utilization of Host Cellular Machinery: As small viruses with limited coding capacity, anelloviruses rely heavily on host cellular machinery for their replication and protein synthesis. They may redirect host metabolic resources for viral production, though the extent of this impact on overall host metabolism is likely minimal given their small genome size.
Potential Influence on Host Cell Metabolism: Some studies suggest that anelloviruses may influence the metabolism of infected cells, potentially affecting cellular processes such as apoptosis, cell cycle regulation, and immune signaling. However, these effects are generally subtle and may vary depending on the specific viral strain and host cell type.
Clinical Relevance
While anelloviruses have not been definitively linked to any specific disease, they have emerging clinical relevance in several areas:
Marker of Anthropogenic Pollution: TTV has been proposed as a marker for detecting human-derived pollution in environmental samples, such as water and soil. Its high prevalence in the human population and resistance to common water treatment methods make it a potential indicator of fecal contamination.
Biomarker for Immune Function: The most significant clinical application of anelloviruses is their potential use as biomarkers for immune system status. TTV viral load has been shown to correlate with the degree of immunosuppression in various clinical settings, including:
Solid Organ Transplantation: In transplant recipients, TTV viral load increases with immunosuppressive therapy and decreases with immune reconstitution. Monitoring TTV levels could help optimize immunosuppressive regimens, potentially reducing the risk of both rejection and opportunistic infections.
Hematopoietic Stem Cell Transplantation: Similar patterns have been observed in stem cell transplant recipients, where TTV viral load may serve as an early indicator of immune reconstitution or graft-versus-host disease.
HIV Infection: TTV viral load has been found to correlate with CD4+ T cell counts in HIV-infected individuals, potentially serving as an additional marker of disease progression.
Potential Therapeutic Target: Although anelloviruses are not currently targeted by antiviral therapies, understanding their interactions with the host immune system could potentially lead to novel therapeutic approaches for modulating immune responses in various clinical contexts.
Interactions with Other Microorganisms
Anelloviruses interact with other components of the human microbiome in several ways:
Coinfection with Other Viruses: Anelloviruses frequently coexist with other viruses in the human host, including hepatitis viruses, herpesviruses, and HIV. These coinfections may involve complex interactions that influence the replication and pathogenicity of both anelloviruses and their viral partners.
Potential Interactions with Bacteria: While direct interactions between anelloviruses and bacteria have not been extensively studied, the presence of anelloviruses in various body sites suggests they may coexist with diverse bacterial communities. The potential influence of these viruses on bacterial populations, or vice versa, remains an area for future research.
Influence on Host Immune Responses: By modulating host immune responses, anelloviruses may indirectly influence the composition and dynamics of other microbial communities within the human microbiome. Changes in immune function associated with anellovirus infection could potentially affect the balance between commensal and pathogenic microorganisms.
Research Significance
Anelloviruses represent a significant area of ongoing research in virology and microbiome science for several reasons:
Model for Viral Persistence: As highly prevalent viruses that establish lifelong infections without causing overt disease, anelloviruses provide valuable models for studying mechanisms of viral persistence and immune evasion.
Biomarker Development: The potential use of anelloviruses, particularly TTV, as biomarkers for immune function represents a promising area for clinical application. Further research is needed to standardize measurement techniques and establish reference ranges for different clinical contexts.
Virome Composition: As major components of the human virome, anelloviruses contribute significantly to its overall composition and diversity. Understanding their role in the virome may provide insights into the broader interactions between viruses, other microorganisms, and the human host.
Methodological Challenges: Research on anelloviruses faces several challenges, including the lack of efficient cell culture systems, animal models, and standardized serological assays. Overcoming these challenges represents an important goal for advancing our understanding of these ubiquitous viruses.
Potential Therapeutic Applications: While anelloviruses themselves may not be targets for antiviral therapy, understanding their interactions with the host immune system could potentially lead to novel approaches for modulating immune responses in various clinical contexts.
In conclusion, anelloviruses represent a fascinating and ubiquitous component of the human virome. Despite their high prevalence, their specific roles in human health and disease remain largely enigmatic. Continued research on these viruses promises to yield valuable insights into viral persistence, host-virus interactions, and the complex dynamics of the human microbiome.