Anellovirus

Introduction

Phylogenetic tree of known anelloviruses.

By Julia Josowitz

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Overview

Anelloviruses are small, circular, single stranded, negative-sense DNA viruses found in blood plasma. While they are not known to cause any harm, high viral loads are associated with immune suppression and diseases such as hepatitis, cancer, and autoimmune diseases (Blatter et al.).The first anellovirus discovered was torque teno virus (TTV) in 1997, and since then it has been found that these viruses are relatively widespread and heterogenous (Spandole et al.). Within the family Anelloviridae there are three known genera: Alphatorquevirus, Betatorquevirus, and Gammatorquevirus. Alphatorquevirus includes TTV, while Betatorquevirus includes torque teno mini virus and Gammatorquevirus includes torque teno midi virus. Anelloviruses that infect animals have also been found in cats, dogs, and even pigs. TTVs are very prevalent in the human population and appear to establish persistent infections, which raises the question of how they evade the host immune system, and almost suggest a commensualist relationship.

TTVs are unenveloped viruses that have a capsid made of 12 pentameric capsomers. Virion particle sizes range from 30 to 50 nm for TTV, but are less than 30 nm for torque teno mini virus (TTMV). The crystal structure of TTV has not been solved and these viruses cannot be grown in vitro due to lack of compatible cell systems. Double stranded replicative intermediates have been found in the bone marrow and liver of humans, suggesting that these cells support replication of the virus. Recent studies have also suggested that the virus may be able to replicate in peripheral blood mononuclear cells under certain conditions (Thom and Petrik).

Genome

The anellovirus genome is made of a circular single stranded DNA molecule that has a GC rich region of 117 nucleotides. Genome size varies, but the TTV genome ranges from 3.6 to 3.9 kb. Of this, there is a .2 kb untranslated region and a 2.6 kb coding region. The untranslated region has been highly conserved, suggesting that it likely plays a role in viral replication. Interestingly, the coding region has two large open reading frames, the first of which encodes 770 amino acid residues and another that encodes large peptides in TTV. Anellovirus is hypothesized to replicate using the rolling-circle method. The genome of anellovirus is very heterogenous, with high divergence. Different genotypes can infect the same host at the same time, even within the same tissue. Researchers hypothesize that this may be due to a high mutation rate in TTV, which is uncommon for DNA viruses, which use the host's own replicative machinery, which is much less error prone. However, research in single stranded DNA viruses such as parvoviruses has found that the single stranded nature of the genome and its ability to encode replication proteins may account for high rates of mutation. Thus, this could explain the high rates of mutation in Anelloviruses.

Recently, it has also been proposed that intra-genomic recombination could account for the heterogeneity of the Anellovirus genome. It has been suggested that TTV has co-evolved with the host for over millions of years, allowing for great variability.

Potential interaction with cytokine signaling

Using computer simulations and synthetic techniques, Kincaid et al. was able to demonstrate anelloviruses likely encode viral micro RNAs (miRNAs). miRNAs are small noncoding RNAs (around 22 nucleotides) that play a role in posttranscriptional gene regulation. Viruses from the herpesvirus and retrovirus families have been found the encode viral miRNAs, and these viruses are also characterized by the ability to establish a persistent infection in their host, much like anelloviruses. It has also been suggested that viral miRNAs may play a role in immune evasion.

Kincaid et al. developed computational methods to predict the possibility of miRNAs from the primary sequence of genes. They identified a diverse group of miRNAs encoded by TTVs, and by engineering recombinant TTVs capable of expressing an RNA transgene in addition to the miRNA, they were able to identify a direct target of TTV miRNA, the gene N-myc interactor (NMI). NMI is a gene that modulates interferon and cytokine signaling. It is stimulated by interferon and has previously been associated with viral induced apoptosis. The authors suggest that the TTV miRNA helps the virus modulate the immune system, by targeting NMI to inhibit interferon and promote immune evasion. However, while strong possible miRNA candidates were observed in all five groups of human TTVs, none were observed in TTMDVs or TTMVs.

Correlation with transplant outcomes

Recent research suggests that anellovirus loads could be used as a predictor of transplant outcomes. High levels of anellovirus are associated with immune suppression, while low levels are correlated with immunocompetence. It had previously been found that lung transplant patients had increased anellovirus levels in their bronchoalveolar fluid and in their serum (Young et al.). Additionally, low plasma anellovirus loads have been found to be associated with acute rejection in heart transplant recipients. This makes anelloviruses a potential marker of chronic rejection, as low plasma anellovirus levels may suggest later rejection.

Correlation between relative anellovirus load and acute cellular rejection (ACR) after pediatric lung transplant. Those with higher anellovirus loads than average had a lower chance of rejecting the graft for all time points after transplantation (2017).

Blatter et al. investigated the impact of both alphatorqueviruses and betatorqueviruses on the outcome of lung transplants in a pediatric cohort of 57 children. They hypothesized that high levels of anellovirus in the blood would be associated with lower levels of rejection and an overall better outcome. Additionally, they predicted that different genera of anellovirus might be associated with different outcomes, as previous research found that alphatorqueviruses correlated with fever in children but betatorqueviruses did not.

Correlation between anellovirus load and graft rejection. De Vlaminck et al. found that at all time points, non-rejecting patients had higher anellovirus loads than rejecting patients (2013).

Blatter et al. found that alphatorquevirus levels were higher than betatorquevirus levels in all of the patients, but the load of each increased over the course of the study, which lasted 18 months post transplant. They found that low alphatorquevirus load were associated with acute rejection, while low betatorquevirus levels were correlated with negative long term outcomes, such as death or retransplant. Similar results were found previously by De Vlaminck et al., who observed that from 1 to 16.5 months post-transplant, patients with rejecting outcomes consistently had a lower anellovirus load than non-rejecting patients. Blatter et al. also found distinct phylogenetic clusters of anelloviruses in patients pre-transplant and in controls when compared to post-transplant patients. It is still unclear whether anelloviruses directly interact with the immune system, but this study suggests that anellovirus load can still be a useful biomarker for prediction of transplant outcomes. Additionally, as discussed above, there is evidence that anelloviruses may be able to indirectly effect the immune system via miRNAs.

Interestingly, it appears that while anellovirus loads increase post-transplant and higher loads are correlated with better transplant outcomes, in general anellovirus load correlates with immunosuppression. As a result, it has also been found to correlate with the progression of AIDS in HIV-infected patients. Thom and Petrik found that patients with AIDS consistently had higher anellovirus loads than HIV positive and negative patients. They also found an inverse relationship between the levels of CD4 T cells and anellovirus loads, suggesting that higher viral loads promote immunosuppression.

In patients receiving high dose chemotherapy coupled with autologous stem cell transplantation, an increase in anellovirus load is observed post treatment. Additionally, this increase correlated with an increase in CD8+ T cells, which can help fight cancer. Anelloviral loads returned to baseline around 100 days post transplant, and the authors used this to hypothesize about when patients have returned to immunocompetent status. Anellovirus loads offer an opportunity for clinicans to make informed decisions about when their patients will have the best outcomes for transplants (Focosi et al.).

Conclusion

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References

Blatter JA, Sweet SC, Conrad C, Danziger-Isakov LA, Faro A, Goldfarb SB, Hayes D, Melicoff E, Schecter M, Storch G, Visner GA, Williams NM, Wang D (2018) Anellovirus loads are associated with outcomes in pediatric lung transplantation. Pediatric Transplantation 22(1): 9

De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR (2013) Temporal Response of the Human Virome to Immunosuppression and Antiviral Therapy. Cell 155(5): 1178-1187

Focosi D, Maggi F, Albani M, Macera L, Ricci V, Gragnani S, Di Beo S, Ghimenti M, Antonelli G, Bendinelli M, Pistello M, Ceccherini-Nelli L, Petrini M (2010) Torquetenovirus viremia kinetics after autologous stem cell transplantation are predictable and may serve as a surrogate marker of functional immune reconstitution. Journal of Clinical Virology 47(2): 189-192

Kincaid RP, Burke JM, Cox JC, de Villiers EM, Sullivan CS (2013) A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling. Plos Pathogens 9(12): 14

Spandole S, Cimponeriu D, Berca LM, Mihaescu G (2015) Human anelloviruses: an update of molecular, epidemiological and clinical aspects. Archives of Virology 160(4): 893-908

Thom K, Petrik J (2007) Progression towards AIDS leads to increased torque teno virus and torque teno minivirus titers in tissues of HIV infected individuals. Journal of Medical Virology 79(1): 1-7

Young JC, Chehoud C, Bittinger K, Bailey A, Diamond JM, Cantu E, Haas AR, Abbas A, Frye L, Christie JD, Bushman FD, Collman RG (2015) Viral Metagenomics Reveal Blooms of Anelloviruses in the Respiratory Tract of Lung Transplant Recipients. American Journal of Transplantation 15(1): 200-209

Edited by Julia Josowitz of Joan Slonczewski for BIOL 238 Microbiology, 2018, Kenyon College.