Anelloviruses
Overview
Anelloviruses (AVs) are small, single-stranded circular DNA viruses belonging to the family Anelloviridae. They are among the most common viruses in humans, found in approximately 90% of the adult population worldwide. Despite their ubiquity, anelloviruses remain largely enigmatic, as they have not been definitively associated with any specific disease. These viruses establish persistent infections early in life and remain with the host throughout their lifetime, making them integral components of the human virome.
The Anelloviridae family that infects humans comprises three main genera: Alphatorquevirus (which includes Torque teno virus or TTV), Betatorquevirus (which includes Torque teno mini virus or TTMV), and Gammatorquevirus (which includes Torque teno midi virus or TTMDV). TTV was the first anellovirus discovered in 1997 in a Japanese patient with post-transfusion hepatitis of unknown etiology. Since then, numerous studies have revealed the extensive diversity and widespread distribution of anelloviruses in human populations.
Characteristics
Anelloviruses possess several distinctive characteristics that set them apart from other viral families:
Genome Structure: They have a small, circular, single-stranded DNA genome of negative polarity, ranging from approximately 2.0 to 3.9 kilobases in length. TTV genomes are typically 3.5-3.9 kb, TTMDV genomes are around 2.3 kb, and TTMV genomes are 2.7-2.9 kb.
Virion Morphology: Anelloviruses are non-enveloped viruses with an icosahedral capsid structure. The virion diameter is approximately 18-30 nm.
Genetic Diversity: They exhibit remarkable genetic diversity, with numerous genotypes and subtypes identified within each genus. This diversity is thought to result from high mutation rates and recombination events.
Genomic Organization: The genome contains overlapping open reading frames (ORFs) and an untranslated region. The main ORFs encode proteins involved in viral replication and capsid formation.
Replication Mechanism: Anelloviruses replicate in the cell nucleus using a rolling circle mechanism. They do not encode their own DNA polymerase and rely entirely on host cell machinery for replication.
Tissue Tropism: They display broad tissue tropism and have been detected in various tissues and body fluids, including blood, saliva, urine, feces, bile, liver, bone marrow, cervical tissue, brain, and many others.
Role in Human Microbiome
Anelloviruses are considered core components of the human virome, the collection of all viruses present in or on the human body. The term "anellome" refers to the complete set of anelloviruses that can infect an individual. Key aspects of their role in the human microbiome include:
Early Acquisition: Humans typically acquire anelloviruses early in life, often within the first years of life. Maternal transmission (both vertical and through breast milk) is common, as is horizontal transmission through close contact.
Persistent Infection: Once established, anelloviruses typically persist for life, with no convincing examples of viral clearance from infected individuals.
Diverse Distribution: They are found in virtually all body sites and fluids, with particularly high concentrations in blood and liver tissues.
Dynamic Viral Loads: The viral load of anelloviruses, particularly TTV, fluctuates in response to the host's immune status, with higher loads observed in immunocompromised individuals.
Potential Commensal Relationship: The ubiquity and persistence of anelloviruses, coupled with the lack of clear disease associations, suggest they may have a commensal relationship with their human hosts.
Health Implications
The health implications of anelloviruses remain a subject of ongoing research and debate. While they have not been definitively linked to any specific disease, several potential roles in human health have been proposed:
Immune System Interactions
Immune Status Marker: TTV viral load has emerged as a potential marker for immune system status. Higher viral loads are observed in immunocompromised individuals, such as those with HIV/AIDS, undergoing immunosuppressive therapy, or following organ transplantation.
Immune System Development: Some researchers have suggested that anelloviruses may play a role in the development and maturation of the human immune system, particularly in early life.
Immune Modulation: Anelloviruses encode microRNAs (miRNAs) that may modulate host immune responses, potentially contributing to viral persistence and immune evasion.
Disease Associations
While not primary causative agents, anelloviruses have been investigated as potential cofactors or markers in various conditions:
Liver Diseases: Initially discovered in a hepatitis patient, anelloviruses have been studied in relation to various liver diseases. While not directly causative, they may act as cofactors in disease progression.
Respiratory Infections: Some studies have reported associations between anellovirus loads and respiratory infections, particularly in children.
Cancer: Potential associations with various cancers have been investigated, with some studies suggesting anelloviruses may indirectly influence cancer development through mechanisms such as abnormal gene fusion, immune response modulation, and toll-like receptor activation.
Autoimmune Diseases: Possible connections to autoimmune conditions have been explored, though definitive links remain elusive.
Pregnancy Complications: Some research suggests a potential link between anellovirus colonization and preterm birth.
Metabolic Activities
As viruses, anelloviruses do not have their own metabolism but rely entirely on host cellular machinery for replication and protein synthesis. Key aspects of their metabolic interactions include:
Genome Replication: Anelloviruses use a rolling circle mechanism for genome replication, which occurs in the nucleus of infected cells.
Protein Synthesis: They produce several proteins through alternative splicing of a single pre-mRNA, including the ORF1 protein (the largest protein, involved in viral replication) and several smaller proteins with various functions.
MicroRNA Production: Anelloviruses encode miRNAs that may regulate both viral and host gene expression, potentially influencing various cellular processes.
Host Cell Interaction: They primarily replicate in T lymphocytes but can be found in various cell types throughout the body.
Clinical Relevance
The clinical relevance of anelloviruses is still being elucidated, but several potential applications have emerged:
Immune Status Monitoring: TTV viral load has been proposed as a biomarker for monitoring immune function in transplant recipients and immunocompromised patients. Increasing viral loads may indicate excessive immunosuppression and risk of opportunistic infections.
Biomarker for Disease Risk: Some research suggests that anellovirus loads or specific genotypes might serve as biomarkers for disease risk or progression in certain conditions.
Diagnostic Considerations: The ubiquity of anelloviruses means they must be considered when developing diagnostic tests for other viruses to avoid false positives due to cross-reactivity.
Potential Therapeutic Applications: Understanding the mechanisms by which anelloviruses establish persistent, non-pathogenic infections could inform the development of novel therapeutic approaches for other viral infections.
Interactions with Other Microorganisms
Anelloviruses coexist with numerous other microorganisms in the human body and may engage in various interactions:
Co-infections: Anelloviruses are frequently found alongside other viruses, bacteria, and fungi. The significance of these co-infections is still being investigated.
Viral Interference: Some studies suggest potential viral interference between anelloviruses and other viral infections, where the presence of one virus may influence the replication or pathogenicity of another.
Microbiome Interactions: As part of the human virome, anelloviruses may interact with the bacterial microbiome, potentially influencing microbial community structure and function.
Immune System Modulation: By modulating host immune responses, anelloviruses may indirectly influence the host's interactions with other microorganisms.
Research Significance
Anelloviruses represent a fascinating area of research for several reasons:
Virome Component: As ubiquitous components of the human virome, understanding anelloviruses is essential for comprehending the complete microbial ecosystem of the human body.
Evolutionary Insights: The extensive diversity and widespread distribution of anelloviruses provide insights into virus-host coevolution and adaptation.
Immune System Interactions: Studying how anelloviruses establish persistent infections without causing apparent disease may reveal important mechanisms of immune tolerance and viral immune evasion.
Biomarker Potential: The correlation between anellovirus loads and immune status offers potential applications in clinical monitoring and personalized medicine.
Methodological Challenges: Research on anelloviruses highlights technical challenges in virology, as these viruses have not been successfully cultured in vitro, necessitating the development of alternative research approaches.
Despite decades of research since their discovery, anelloviruses remain enigmatic, with many questions about their biology, evolution, and potential role in human health still unanswered. Continued research into these ubiquitous viruses promises to yield valuable insights into virus-host interactions and the complex ecosystem of the human microbiome.