Vertical transmission of a virus to the fetus may occur during the birth process, in the period soon after birth, or across the placenta prior to birth (Virgin, 2007
). The studies described here involving Syrian golden hamsters indicate that vertical transmission is a possible mode of spread of polyomavirus SV40. These are intriguing findings as SV40 DNA has been detected in infants (Bergsagel et al., 1992
) and recent reports have indicated that the virus is shed in the urine (Vanchiere et al., 2005b
) and stool (Vanchiere et al., 2005a
) of young children. The overall rates of SV40 transmission from mothers to individual offspring in the hamster model under our experimental conditions averaged 14%, a value comparable to those of varicella-zoster virus and human immunodeficiency virus vertical transmission in humans (2-20% and 13-30%, respectively) (Blanche et al., 1989
; Paryani and Arvin, 1986
), but higher than those reported for cytomegalovirus and West Nile virus in humans (0.2% to 4%, respectively) (Demmler, 1991
; Paisley et al., 2006
). The frequency of SV40-positive litters following inoculation of pregnant hamsters was high at 57% (8 of 14 litters with one or more positive progeny).
This study was not designed to study transplacental transmission in detail, but we did detect virus transmission in 1 of 5 litters. This was lower than reported for murine polyoma virus in mice (6 of 7 litters, 86%) (Zhang et al., 2005
), perhaps reflecting differences in experimental conditions or in maternal or viral factors that affect the establishment of infection. One difference is that the Syrian golden hamsters are outbred, making it likely that they exhibit broader individual variations in susceptibilities to infection than inbred mice.
Although it was assumed in the past that hamsters are nonpermissive hosts for SV40, recent evidence indicates that SV40 can infect and undergo replication in some hamsters. In a previous study, infectious SV40 was rescued from 39% of tumor cell lines established from primary tumors induced by SV40 (Sroller et al., 2008
). Tumors from which the cell lines were established had arisen 5-8 months p.i., making it highly unlikely that residual input SV40 was resident in the tumors in vivo and survived during subculture of the cell lines in vitro. This observation was compatible with earlier reports of recovery of infectious virus and/or infectious viral DNA from SV40 tumor cells (Black and Rowe, 1964
; Boyd and Butel, 1972
; Gerber, 1964
; Sabin and Koch, 1963
). Many virus-inoculated, tumor-free animals developed antibodies to T-ag that persisted for one year following either intraperitoneal or intravenous exposure (McNees et al., 2008
; Sroller et al., 2008
). The percentage of T-antibody responders among tumor-free hamsters was higher for those inoculated with viruses having complex regulatory regions as compared to those with simple enhancers. We believe induction of durable T-antibodies in the absence of tumor formation reflects synthesis of T-ag during virus infection and that viruses with complex enhancers replicate more abundantly in vivo than those with simple enhancers. SV40 regulatory region rearrangements were detected in several SV40-induced tumors (Sroller et al., 2008
), and it has been proposed that such rearrangements reflect recombination during viral DNA replication (Cubitt, 2006
; Yogo and Sugimoto, 2001
). In this study, SV40 strains with complex regulatory regions were vertically transmitted significantly more frequently than strains with simple enhancers. Our interpretation is that the 2E viruses replicated to higher titers, increasing the likelihood of transmission. Maternal animals exhibited a rise in viral load from day 2 p.i. followed by viral persistence in maternal spleen, kidney and WBCs through day 24 (the latest time point examined), plus the production of anti-T-ag antibodies. These analyses provided evidence of SV40 replication in hamsters and identified tissues that can be virus positive following IP inoculation.
We postulate that higher viral loads in the mother increase the potential for vertical transmission of polyomavirus. There was a statistically significant higher frequency of transmission of virus to progeny from mothers infected with virus with complex enhancer structures than with simple enhancers (). The frequent detection of SV40 DNA in brain tissue of progeny is compatible with other studies suggesting that SV40 can be neurotropic (Bergsagel et al., 1992
; Lednicky et al., 1995a
; Lednicky and Butel, 2001
The SV40-infected maternal hamsters had detectable virus in tissues that might serve as sources of virus for transmission to their young after birth, including the kidney (urine) and lung (respiratory droplets). It is of interest that lung tissue was sometimes positive in progeny animals, raising the possibility that some polyomavirus infections might occur via the respiratory route. It is expected that blood would be the route of fetal infection in utero. Compatible with that premise, SV40 was detected in the blood of maternal hamsters. It is noteworthy that in the case in which transplacental transmission was documented, there had been a longer duration p.i. prior to fetal harvest than in the other litters tested. In addition, the placentas from that litter had significantly higher viral loads than those from litters in which transmission was not detected, suggesting that placental viral loads may impact transmission to the fetus or may reflect overall viral loads in those maternal animals.
Any long-term effects of SV40 vertical transmission in progeny animals were not addressed in this study. However, none of 43 animals held for 6 months developed neoplasms. This finding contrasts with a previous report that 43-54% of progeny from SV40-inoculated pregnant hamsters developed tumors (Rachlin et al., 1988
). There were several differences between the two studies that may explain the results. The hamsters were obtained from different sources, the pregnant animals were inoculated earlier during gestation in the Rachlin study than in ours, and they observed the animals for 10 months as compared to only 6 months in our study. SV40 tumor latency and tumor frequency are virus-dose dependent (Gerber and Kirschstein, 1962
; Girardi et al., 1963
). It is possible that earlier gestational inoculation led to higher amounts of virus being transmitted to the fetuses in the Rachlin study, increasing their effective exposure dose; that exposure, coupled with the longer period of observation, perhaps made it more likely that tumors could be observed.
Our findings of SV40 vertical transmission in the hamster model differ from cross-sectional serological surveys in captive rhesus macaques (Minor et al., 2003
) and humans (Engels et al., 2004
) that suggested that vertical transmission had not occurred. Serologic analyses of BKV in humans led to the conclusion that transplacental transmission was not a mode of spread for this polyomavirus (Andrews et al., 1983
; Brown et al., 1984
). Recent molecular-based studies have differed in evidence for transplacental transmission of human polyomaviruses (Boldorini et al., 2008
; Pietropaolo et al., 1998
). Additional studies are warranted to clarify the possible vertical transmission of polyomavirus in humans.
It is known that SV40 strains may have different growth properties in vitro (Lednicky et al., 1995b
; Lednicky and Butel, 2001
) and recent observations have proven variation in oncogenic potential in vivo (Sroller et al., 2008
; Vilchez et al., 2004
). This study shows that viral strains can differ in the biologic property of frequency of vertical transmission, as well. All three examples reflected differences in the regulatory region structures of the viral variants. This suggests that the viral regulatory region can be considered a determinant that may affect pathogenesis of infection and disease in vivo.
Animal models have been powerful experimental tools for studies of human disease pathogenesis, including cancer (Mizgerd and Skerrett, 2008
; Virgin, 2007
). Syrian golden hamsters are uniquely susceptible to a variety of intracellular pathogens. They serve as infection models that mimic human disease for several parasites, including Leishmania
(Melby et al., 2001
) and Opistorchis
(Jittimanee et al., 2007
). Hamsters are permissive immunocompetent animal models for infections by numerous viruses able to infect humans, such as herpesviruses (van Ekdom et al., 1987
), vaccinia virus (Nelles et al., 1981
), adenovirus (Thomas et al., 2006
), rubella virus (Rayfield et al., 1986
), measles virus (Vanchiere et al., 1995
), Nipah virus (Wong et al., 2003
), arenaviruses (Gowen et al., 2005
), flaviviruses (Siirin et al., 2007
; Tesh et al., 2005
), and hantaviruses (Campen et al., 2006
). As described above, it appears that SV40 can replicate in hamsters. SV40 has long been recognized for its ability to induce tumors in hamsters (Butel et al., 1972
; Butel, 2000
; Butel and Lednicky, 1999
; Cicala et al., 1992
; Diamandopoulos, 1973
) and the types of tumors that develop include the same spectrum of malignancies as the human cancers associated with SV40 (Butel, 2008
; Gazdar et al., 2002
). The hamster model has shown that asbestos and SV40 can cooperate in induction of mesotheliomas (Kroczynska et al., 2006
). Similarities have been found between humans and hamsters with respect to tissues that can harbor SV40 and the spectrum of malignancies associated with the virus. Hamsters are especially well-suited for future comparative studies of the effects of viral strain genetic differences on pathogenesis of SV40 infections and disease.
In conclusion, the results described here show that vertical transmission by polyomavirus SV40 can occur in susceptible hosts, that the viral regulatory region is a determinant of transmission, and that SV40 appears to replicate in hamsters. The possibility of vertical transmission of polyomaviruses in humans should be considered.