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Letter
Small Anellovirus in Hepatitis C Patients and Healthy
Controls
Elisabetta Andreoli,* Fabrizio Maggi,* Mauro Pistello,*
Silvia Meschi,* Marialinda Vatteroni,* Luca Ceccherini Nelli,* and Mauro
Bendinelli*
*University of Pisa, Pisa, Italy
Suggested citation for this article
To the Editor: Torquetenovirus (TTV) and
torquetenominivirus (TTMV) are characterized by a small, negative-sense,
circular, single-stranded DNA genome and by an extraordinary ability to produce
chronic plasma viremia. Indeed, >80% of humans harbor variably high viral
loads of TTV, TTMV, or both, in plasma, regardless of geographic provenance,
age, sex, and health conditions (1). Currently, TTV and
TTMV are classified as distinct species in the floating (although closely
linked to the family Circoviridae) genus Anellovirus, but their
extreme genetic heterogeneity and some distinctive features in genomic
organization have led some to suggest that they should be classified as an
independent family (2,3). Most recently, after examining
serum specimens from patients with symptoms of an acute viral infection by
using DNase sequence-independent single-primer amplification, Jones et al. (4)
identified, among other viruses, 2 novel TTV- and TTMV-like agents. Because of
their even smaller genomes (≈2.4 and
2.6 kb vs. 3.6–3.8 kb for TTV and 2.8–2.9 kb for TTMV), these agents were named
small anelloviruses (SAVs).
Because tissue culture and serologic methods are not yet
available, diagnosis of anellovirus infection relies exclusively on viral DNA
detection. We tested 55 Italian hepatitis C patients (mean age 56 ± 14 years, male/female ratio 30/25, 53 TTV
positive) and, for comparison, 35 healthy donors (mean age 36 ± 12 years, male/female ratio 17/18, 33 TTV
positive) for SAV in plasma by using the polymerase chain reaction (PCR)
primers described by Jones et al. (4),
followed by direct amplicon sequencing. To increase assay sensitivity, a
heminested PCR format was adopted that used a sense primer designed in a
segment of the untranslated region that is highly conserved among all
anelloviruses (5´-TCAAGGGGC AATTCGGGCT-3´). We found 5 positive results among the
hepatitis C patients (9.1%, all of whom were TTV positive) and 3 positive
results among healthy controls (8.6%); and all were confirmed by sequence data.
The amino acid sequences inferred from the coding segment of
the amplicon of SAV in this study and the corresponding sequences of the 10 SAV
in GenBank at the time of this writing were then aligned with representative
TTV and TTMV sequences (Appendix Figure 1). This method allowed us to identify
the motif WX7HX3CXCX5H, which is highly
characteristic of the open reading frame 2 (ORF2) of anelloviruses (5),
in all SAVs. SAV sequences, as well as a large number of TTVs and all TTMVs,
were then used to construct a phylogenetic tree and to calculate the extent of
genetic divergence within SAV, TTV, and TTMV. Although a precise phylogenetic
description will require the analysis of full-length ORF2, the SAV sequences
clustered quite separately from those of TTV and TTMV, and the extent of
divergence observed among SAV was huge and in the same range as among TTV or
TTMV. Furthermore, SAVs obtained from hepatitis C patients and healthy
participants were intermingled (Appendix Figure 2).
While this study was under way, Biagini et al. reported a
12% prevalence of SAV viremia in French blood donors (6). Our
results confirm the high prevalence of SAV viremia in healthy persons and
extend the finding to hepatitis C patients. Our data, combined with those of
Biagini et al., indicate that, since SAV clusters separately from previously
identified anelloviruses, it should be considered a distinct species (or
possibly genus). This would increase the already high genetic diversity of
anelloviruses, further arguing for the appropriateness of creating a separate
viral family.
Because the clinical and viral parameters of hepatitis C in
SAV-positive patients were not significantly different from those in the
SAV-negative patients (data not shown), our results suggest that, similar to
TTV (7),
SAV has little or no effect on the course of hepatitis C. Although
anelloviruses have not yet been definitely linked to any specific disease,
evidence is growing that they might be involved in acute respiratory diseases
in children (8,9).
Furthermore, a florid TTV replication in the respiratory tract correlated with severity
of lung impairment in children with asthma (10). A
precise appreciation of the wide range of viruses classified within the
anelloviruses is a prerequisite to understanding such disease associations and
the disease-inducing potential of these viruses in general.
References
- Bendinelli M, Pistello M, Maggi F, Fornai C, Freer G, Vatteroni ML. Molecular properties, biology and clinical implications of TT virus, a recently
identified widespread infectious agent of man. Clin Microbiol Rev.
2001;14:98–113.
- Hino S. TTV, a new human virus with single stranded circular DNA genome. Rev Med Virol.
2002;12:151–8.
- Biagini P, Todd D, Bendinelli M, Hino S, Mankertz A, Mishiro S, et al. Anellovirus. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy, 8th report of the International Committee for the Taxonomy of Viruses. New York: Elsevier/Academic Press; 2004. p. 335–41.
- Jones MS, Kapoor A, Lukashov VV, Simmonds P, Hecht F, Delwart E. New DNA viruses identified in patients with acute viral infection syndrome. J
Virol. 2005;79:8230–6.
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anellovirus") in French blood donors. Arch Virol. 2006;151:405–8.
- Nishizawa Y, Tanaka E, Orr K, Rokuhara A, Ichijo T, Yoshizawa K, et al. Clinical impact of genotype 1 TT virus infection in patients with chronic
hepatitis C and response of TT virus to alpha-interferon. J Gastroenterol
Hepatol. 2000;15:1292–7.
- Biagini P, Charrel RN, de Micco P, de Lamballerie X. Association of TT virus primary infection with rhinitis in a newborn. Clin
Infect Dis. 2003;36:128–9.
- Maggi F, Pifferi M, Fornai C, Andreoli E, Tempestini E, Vatteroni ML,
et al. TT virus in the nasal secretions of children with acute respiratory diseases:
relations to viremia and disease severity. J Virol. 2003;77:2418–25.
- Pifferi M, Maggi F, Andreoli E, Lanini L, De Marco E, Fornai C, et al. Associations between nasal torquetenovirus load and spirometric indices in
children with asthma. J Infect Dis. 2005;192:1141–8.
Suggested citation
for this article:
Andreoli E, Maggi F, Pistello M, Meschi S, Vatteroni M, Ceccherini Nelli
L, et al. Small anellovirus in hepatitis C patients and healthy controls
[letter]. Emerg Infect Dis [serial on the Internet]. 2006 Jul [date cited].
Available from http://www.cdc.gov/ncidod/EID/vol12no07/06-0234.htm
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