The newly described human metapneumovirus (hMPV) is reported here to be more commonly associated with lower respiratory tract disease. The present study examined nasal swab specimens from 90 infants with acute respiratory tract infections in Pisa, Italy, over a period of three respiratory virus seasons. The incidence of infection varied in each of the 3 years, with the rates of positivity for hMPV being 7% in 2001 but 37 and 43% in 2000 and 2002, respectively. hMPV was noted to occur seasonally in a pattern typical of the frequency of occurrence of respiratory syncytial virus. More than one-half (14 of 23) of the infants infected with hMPV had bronchopneumonia. One-third (9 of 23) of the hMPV-infected patients were also infected with another respiratory virus, a relationship that has not previously been reported. Mixed infections did not account for a higher percentage of cases of bronchopneumonia than hMPV infection alone did. Furthermore, 7 of 17 infants whose plasma was also tested for hMPV RNA were demonstrated to have virus in both nasal swab and blood specimens. The study indicates that hMPV is seen as commonly as other respiratory viruses, may be associated with severe respiratory disease in infants, can establish mixed infections with other respiratory viruses, and has a seasonal occurrence.

The natural history and pathogenic potential of the recently identified TT virus (TTV) are currently a matter of intensive investigation. In an attempt to shed some light on these issues, nasal and blood specimens of 1-to 24-month-old children hospitalized with a clinical diagnosis of acute respiratory disease (ARD) were examined for the presence, load, and genetic characteristics of TTV. The results have indicated that at least in young children, the respiratory tract not only represents a route by which abundant TTV can be shed into the environment but also may be a site of primary infection and continual replication. Although we found no compelling evidence that TTV was the direct cause of ARD in some of the children studied, the average loads of TTV were considerably higher in patients with bronchopneumonia (BP) than in those with milder ARD, raising interesting questions about the pathophysiological significance of TTV at this site. Furthermore, group 4 TTV was detected almost exclusively in children with BP.TT virus (TTV)-a small, nonenveloped virus with a singlestranded, negative-polarity, circular DNA genome of 3.8 kbwas initially thought to be a circovirus similar to chicken anemia virus, porcine circovirus, and other viruses of animals, but it is now under consideration as the possible type species of an independent virus family (17,18,34,35). The taxonomy of the vast array of related viral agents that have been identified in humans since the first description of TTV by Nishizawa et al. in 1997 (21) is also uncertain. Recently, however, Okamoto and Mayumi (22) have divided TTV isolates into at least four phylogenetic clusters differing by over 40% at the nucleotide level: group 1 has the original TTV isolate as the prototype and includes genotypes 1 to 6; group 2 has PMV as the prototype and comprises genotypes 7, 8, 17, 22, and 23; group 3 has SANBAN and SENV as representative isolates and includes genotypes 9 to 16 and 18 to 20; and group 4 has YONBAN as the prototype and includes genotype 21. Furthermore, while the present report was in preparation, the same group identified several novel genotypes within group 4 TTV as well as members of a proposed fifth group (26). Additional related viruses are more dissimilar due to their smaller genome (2.8 kb) and are presently designated TTV-like minivirus or TLMV (6,33,34).The natural history and pathogenic potential of TTV are currently the subject of active investigation. From the epidemiological standpoint, evidence has accumulated that TTV viremia is extremely common in the general population worldwide, starting from early childhood (1,5,10,26,27), implying the existence of a very efficient means of transmission, and the observation that infectious TTV is shed in the feces has led to the suggestion that the fecal-oral route is the most likely one (36). With regard to the life cycle in infected hosts, both selflimited and persistent systemic TTV infections have been described (reviewed in reference 5) and chronic TTV viremia has been shown to result fro...

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TT virus (TTV) is a recently identified widespread DNA virus of humans that produces persistent viremia in the absence of overt clinical manifestations. In an attempt to shed light on the dynamics of chronic infection, we measured the levels of TTV in the plasma of 25 persistently infected patients during the first 3 months of alpha interferon (IFN-␣) treatment for concomitant hepatitis C virus (HCV) infection. The first significant decline of TTV loads was observed at day 3 versus day 1 for HCV. Subsequently, the loads of TTV became progressively lower in most patients, but some initial responders relapsed before the end of the follow-up, suggesting that at least in some subjects the effects of IFN on TTV can be very short-lived. No correlation between the responses of TTV and HCV to therapy was found. Fitting the viremia data obtained during the first week of treatment into previously developed mathematical models showed that TTV sustains very active chronic infections, with over 90% of the virions in plasma cleared and replenished daily and a minimum of approximately 3.8 ؋ 10 10 virions generated per day. Low levels of TTV were occasionally detected in the peripheral blood mononuclear cells of patients who had cleared plasma viremia, thus corroborating previous results showing that these cells may support TTV replication and/or persistence.

Active infection with torquetenovirus (TTV) has been associated with an increased severity of diseases in which inflammation plays a particularly important pathogenetic role. Here, we report that cloned DNA of a genogroup 4 TTV (ViPiSAL) is an activator of proinflammatory cytokine production by murine spleen cells and that the effect is mediated via toll-like receptor (TLR)9. The same DNA also increased the levels of proinflammatory cytokines induced by two well-characterized TLR9 stimulants. Finally, in silico analyses of the genomes of ViPiSAL and other TTVs revealed marked differences in the representation of CpG motifs known to be most effective at activating immune cells via TLR9. These findings demonstrate for the first time that at least one TTV isolate has the potential to stimulate and co-stimulate inflammatory responses.