A global epidemic increase of an HPV-induced tonsil and tongue base cancer - potential benefit from a pan-gender use of HPV vaccine.

In 2007, human papillomavirus (HPV) type 16 was finally recognized as a risk factor, besides smoking and alcohol, for oropharyngeal squamous cell carcinoma (OPSCC), including tonsillar squamous cell carcinoma (TSCC), by the International Agency for Research against Cancer. Just before, in 2006, the Food and Drug Administration had approved Gardasil, the first vaccine against HPV16, 18, 6 and 11, for preventive vaccination women against cervical cancer. Concurrently, some Western countries, where smoking was decreasing, disclosed an epidemic increase in the incidence of OPSCC, especially of TSCC and base of tongue cancer (BOTSCC), together accounting for 80-90% of all OPSCCs, and mainly affecting men. The epidemic was later revealed to be due to a rise in HPV-positive cases, and scientists in the field suggested HPV vaccination also of boys. Globally, there are roughly 96 000 incident OPSCC cases/year of which 20-24% are caused by HPV, thereby accounting for around 22 000 OPSCC cases annually. Of these cases, 80-90% are due to HPV16 infection and would be prevented with the presently registered HPV vaccines. In Western countries, such as Sweden (with almost 400 TSCC and BOTSCC cases per year) and the United States, HPV prevalence in OPSCC is higher and around 70%. HPV vaccination of girls has been initiated in many countries, and the vaccines have been efficient and their side effects limited. HPV vaccination of boys has, however, been the exception, but should definitely not be delayed any further. It would benefit both girls and boys directly, and result in better and more robust herd immunity. Today, we have the possibility to eliminate several high-risk HPV types in the younger generations and avoid more than 600 000 cancer cases annually worldwide, and this possibility should be embraced by offering global pan-gender HPV vaccination.

Studies of human polyomaviruses, with HPyV7, BKPyV, and JCPyV present in urine of allogeneic hematopoietic stem cell transplanted patients with or without hemorrhagic cystitis.

BACKGROUND: BK polyomavirus (BKPyV) can cause hemorrhagic cystitis (HC) in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients and polyomavirus-associated nephritis in renal transplant patients, while JC polyomavirus (JCPyV) can generate progressive multifocal leukoencephalopathy in immunocompromised individuals. Since 2007, additional human polyomaviruses (HPyVs) have been identified. In this study, we examined the urines of allo-HSCT patients for possible presence of polyomaviruses BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, HPyV6, HPyV7, TSPyV, HPyV9, and HPyV10 (MWPyV). METHODS: A total of 185 urinary samples obtained 2002-2007 from 105 allo-HSCT patients, 32/105 with HC, were tested for the above-listed HPyVs by a bead-based multiplex assay. Of these, 142 urine samples had previously been tested for BKPyV and JCPyV by nested polymerase chain reaction (PCR). RESULTS: Aside from BKPyV and JCPyV, which dominated, HPyV7 was detected in 5 BKPyV-positive urinary samples from 1 patient. The multiplex assay was more sensitive and specific than the nested PCR. BKPyV and/or JCPyV were found in all but 1 of the previously BKPyV- or JCPyV-positive samples, although 6 previously BKPyV-positive cases were now JCPyV-positive or the reverse. Furthermore, 18/79 previously negative samples were found to be BKPyV and/or JCPyV positive, and a total of 21 double infections were found. Lastly, in 1/29 HC patients, only JCPyV was detected. CONCLUSION: HPyV7 was found for the first time in urine of an allo-HSCT patient, and BKPyV and JCPyV were more commonly found in urine samples using the bead-based assay compared to testing by nested PCR. Finally, only JCPyV was detected in the urine of 1 HC patient.

Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer.

BACKGROUND: The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent. METHODS: The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients. RESULTS: LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status. CONCLUSIONS: Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer.

BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts.

The influence of conditioning regimen, donor background and HLA matching on development of BK virus (BKV)-associated haemorrhagic cystitis (HC) was examined in 175 allogeneic haematopoietic stem cell transplant (HSCT) patients, undergoing 179 HSCT events. Twenty-seven patients presented late-onset HC, and BK viruria was verified in 23/27 HC events. Seventy-one (40%) HSCTs were performed with myeloablative conditioning (MC), 108 (60%) were performed with reduced intensity conditioning (RIC), 66 (37%) were performed with a related donor (RD) grafts and 113 (63%) with an unrelated donor (URD) graft. BK viruria was more common during HC, than non-HC events, after MC as compared to RIC (both P<0.001), and with an HLA-mismatched donor (P<0.01). By multivariate logistical regression analysis, independent risk factors for HC were BKV (OR 6.7; 95% CI 2.0-21.7; P=0.001), MC (OR 6.0; 95% CI 2.1-17.3; P<0.001) and URD (OR 3.4; 95% CI 1.1-10.6; P=0.03). However, when analysing HSCT performed with URD or RD grafts separately, BKV (OR 8.5; 95% CI 1.8-19.3; P=0.004) and MC (OR 5.9; 95% CI 1.3-11.3; P=0.009) increased the risk for HC only with a URD, but not with an RD graft.

Detection of mutant-specific responses by macrophage migration inhibition reactions induced by wild-type and mutant polyoma viruses and polyoma virus-infected cells.

Macrophage migration inhibition responses of mice immunized with mutant polyoma viruses or with cells transformed and/or infected by them have been studied. The macrophage migration inhibition reaction revealed individual differences. In several cases, mice immunized with a mutant virus responded preferentially or exclusively to extracts of cells transformed or infected with the corresponding mutant. Moreover, in the macrophage migration inhibition test, mutant viruses were usually less immunogenic than were the corresponding transformed-infected cells.

Detection of a polyoma virus-induced tumor-associated membrane antigen in mouse cells by the macrophage migration inhibition test.

Soluble membrane fractions derived from polyoma tumor cells trigger lymphocytes, derived from polyoma-immunized animals, but not from nonimmunized controls, to release the lymphokine, macrophage migration-inhibitory factor. The reaction can be blocked by sera from polyoma-bearing animals. Absorption of these sera with polyoma cells, but not with nonpolyoma cell lines, abrogates this activity. These findings suggest that there is a polyoma virus-induced membrane component that can induce polyoma-specific macrophage migration inhibition.

Physicochemical and morphological characterization of a new allotransplantable mammary carcinoma ascites subline, TA3-St/ticol/-A.

The TA3-St/ticol ascites cell (I), immunoselected from the strain-specific TA3-St mammary carcinoma ascites cell of the strain A mouse for decreased H-2a antibody-binding capacity, underwent a spontaneous transition in vivo to a new cell line, TA3-St/ticol/-A (II). Line II was more allotransplantable than was the parental line (line I), and its absorptive capacity for anti-H-2a antibody was manyfold less than line I. Disruption of line II cells by lyophilization did not increase the absorptive capacity, in contrast to its marked enhancement in the TA3-Ha ascites cell under similar conditions. An explanation for the enhanced allotransplantability of line II may be related to either a loss of H-2a antigens or altered macromolecular structures at the cell surface: sialic acid, consisting of 93% N-glycolylneuraminic acid for line II and 9% for line I; altered chemical structures of cell surface glycoproteins, particularly a high-molecular-weight glycoprotein present in much greater proportion in line II than in line I; a macromolecular complex released by a protease from line I, but not line II; and I being agglutinable by concanavalin A, but not line II. Electron microscopy showed line II to be more pleomorphic and less rounded than was line I. Under high-resolution electron microscopy, the cell surfaces of both allotransplantable cells, lines II and I, exhibited thin filamentous material, material not observed at the surface of the nonallotransplantable TA3-St ascites cell.

Cell surface characteristics of an allotransplantable TA3 ascites subline resulting from a process of immunoselection.

Comparison of the cell surface characteristics of the parental strain-specific TA3-St ascites cell (I) of the strain A mouse and the more allotransplantable TA3-St/ticol ascites cell (II), immunoselected for reduced absorption of anti-H-2a antibody from Cell I, revealed the following. Cell II, like Cell I, possessed no detectable epiglycanin at its surface, as neither cell absorbed more than 0.5% as much of the antiepiglycanin antibody as was absorbed by the epiglycanin-containing allotransplantable TA3-Ha ascites cell. Tritium-labeled glycoproteins, with polyacrylamide slab gel electrophoresis with sodium dodecyl sulfate and with isoelectric focusing of detergent-treated cells, exhibited marked quantitative differences, but qualitative differences were not established. Glycopeptides cleaved from each cell by proteolysis and fractionated by gel filtration gave similar elution profiles, and the column fractions possessed similar carbohydrate and amino acid compositions. Less sialic acid (170 micrograms/10(9) cells) was removed by neuraminidase from Cell II than from Cell I (270 micrograms/10(9) cells), and the compositions (9% N-glycolylneuraminic acid for Cell II and 20% for Cell I) were different. Transmission and scanning electron microscopy showed rough irregular folds and ridges on the surfaces of each cell, but Cell II appeared more pleomorphic and less rounded than did Cell I. High-resolution transmission electron microscopy showed filamentous material at the surface of Cell II, but not at the surface of Cell I.

Low incidence of acute graft-versus-host disease, using unrelated HLA-A-, HLA-B-, and HLA-DR-compatible donors and conditioning, including anti-T-cell antibodies.

BACKGROUND: Using unrelated bone marrow, there is an increased risk of graft-versus-host disease (GVHD). METHODS: HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow was given to 132 patients. The diagnoses included chronic myeloid leukemia (n=43), acute lymphoblastic leukemia (n=29), acute myeloid leukemia (n=27), myelodysplastic syndrome (n=4), lymphoma (n=3), myeloma (n=1), myelofibrosis (n=1), severe aplastic anemia (n=12), and metabolic disorders (n=12). The median age was 25 years (range 1-55 years). HLA class I was typed serologically, and class II was typed by polymerase chain reaction using sequence-specific primer pairs. Immunosuppression consisted of antithymocyte globulin or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporine. RESULTS: Engraftment was seen in 127 of 132 patients (96%). Bacteremia occurred in 47%, cytomegalovirus (CMV) infection in 49%, and CMV disease in 8%. The cumulative incidences of acute GVHD > or = grade II and of chronic GVHD were 23% and 50%, respectively. The 5-year transplant-related mortality rate was 39%. The overall 5-year patient survival rate was 49%; in patients with metabolic disorders and severe aplastic anemia, it was 61% and 48%, respectively. The disease-free survival rate was 47% in patients with hematological malignancies in first remission or first chronic phase and 38% in patients with more advanced disease (P=0.04). Acute GVHD was associated with early engraftment of white blood count (P=0.02). Poor outcome in multivariate analysis was associated with acute myeloid leukemia (P=0.01) and CMV disease (P=0.04). CONCLUSION: Using HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow and immunosuppression with antithymocyte globulin, methotrexate, and cyclosporine, the probability of GVHD was low and survival was favorable.

p53 overexpression in normal and dysplastic tissues adjacent to p53 negative squamous cell carcinomas of the head and neck.

p53 overexpression was present in the normal or dysplastic epithelium, but absent in the adjacent invasive cancers of five patients with head and neck squamous cell carcinomas (HNSCC), when p53 immunostaining (IHC) was performed. In three of the five p53 immunoreactive dysplasias and adjacent p53 negative invasive cancers single stranded conformation polymorphism (SSCP) results from exon 7 and 8 were also obtained. Bandshifts in exon 7 were detected in two dysplasias, and bandshifts in exon 8 were found in a third. Sequencing of exon 7 in the first dysplasia with bandshift indicated a deletion of codon 241-242 (loss of CT) resulting in a frame shift. In the second dysplasia with bandshift a mutation was observed in codon 244 resulting in a Gly-->Arg substitution in the protein sequence. In the adjacent IHC p53 negative invasive cancer lesions, no bandshifts could be observed by SSCP, and sequencing did not reveal any mutated p53. WAF1/p21 (IHC) expression was assayed to study p53 function. Image cytometry (ICM) DNA analysis, estimating genetic instability, showed progress in DNA aberration for invasive cancer lesions as compared with the dysplasias. Human papillomavirus (HPV DNA) was not detected by a polymerase chain reaction (PCR) in any of the five cancers thus excluding possible p53 degradation caused by HPV protein. In conclusion, the finding of p53 mutations in mild, moderate, and severe dysplasia indicates that p53 mutation, not only p53 immunoreactivity, can be an early event in HNSCC carcinogenesis. The lack of p53 immunoreactivity in the invasive cancers adjacent to p53 positive dysplasias could possibly be attributed to loss of the mutant allele, or clonal heterogeneity.

Overrepresentation of point mutations in the Sp1 site of the non-coding control region of BK virus in bone marrow transplanted patients with haemorrhagic cystitis.

BACKGROUND: Haemorrhagic cystitis (HC) in allogeneic bone marrow transplanted (BMT) patients is associated with reactivation of BK virus (BKV) manifested as BK viruria. However, it has been suggested that BKV reactivation alone is not responsible for HC, since BKV can be detected in the urine of 50-90% of all adult BMT patients. OBJECTIVES: In the present study, we analysed if BK viruses with specific mutations in the non-coding control region (NCCR) or in the region encoding the major capsid protein (VP1) were more frequently associated to the appearance of HC in BMT patients. STUDY DESIGN: The NCCR and the region encoding VP1 of BKV excreted in the urine from 25 BMT patients, 16 with and nine without HC, were sequenced by an ABI Prism Big Dye terminator cycle sequencing ready reaction kit. RESULTS AND CONCLUSIONS: A statistically significant (P=0.019) overrepresentation of C to G mutations within the NCCR Sp1 binding site was observed in 7/16 (43%) patients with HC (six cases at position 249 (P=0.035) and one case at position 251), as compared with 0/9 (0%) of the patients without HC. Major differences were not observed in the VP1 sequences of patients with and without HC. BKV WW and WWT-variants as well as BKV subtype I were most commonly encountered in both groups of patients. In conclusion, C to G point mutations, within the BKV NCCR Sp1 binding site, were significantly more common in patients with HC, suggesting that these mutations may be indicative for the clinical diagnosis of HC and could influence the virulence of the virus.

Presence of human polyomavirus DNA in the peripheral circulation of bone marrow transplant patients with and without hemorrhagic cystitis.

In BMT patients, shedding of BK virus (BKV) in the urine has been strongly but not absolutely correlated to hemorrhagic cystitis (HC). The possible presence of human polyomaviruses in peripheral blood leukocytes (PBLs), plasma, serum and urine in BMT patients and an association with HC was investigated by a nested PCR assay. Samples from allogeneic BMT patients with and without HC as well as from autologous BMT patients were analyzed. Human polyomaviruses were detected in urine and blood samples of both allogeneic and autologous BMT patients with and without HC. An association between the presence of a specific human polyomavirus in blood and HC was thus not observed.

Loss of seroreactivity against human papillomavirus (HPV) in bone marrow transplant recipients.

Sera from 19 autologous and 35 allogeneic bone marrow transplant (BMT) patients at Huddinge University Hospital were analyzed by different ELISA assays before and 1 year after BMT for the presence of IgG antibodies towards human papillomavirus (HPV). One assay was a peptide-based enzyme-linked immunoadsorbent assay (ELISA). These peptides were derived from the amino acid sequences of the two major viral capsid proteins of HPV 16, p(31) L1 and (p49) L2. The other was an ELISA using HPV-type 16 virus-like particles (VLPs) as antigens. Before BMT 13/19 autologous and 14/35 allogeneic BMT patients were IgG positive towards p49 (L2). Reactivity to p31 (L1) was less frequent and was only observed in 7/19 autologous and 3/35 allogeneic BMT patients. One year after BMT 1/4 of the autologous and 2/3 of the allogeneic BMT patients who were IgG positive to p49 (L2) lost these antibodies as measured by the peptide ELISA assay. Regarding IgG reactivity to p31 (L1), one of the seven p31 (L1) positive autologous BMT patients and all three of the p31 (L1) positive allogeneic BMT patients lost this reactivity 1 year after BMT. Of all the 19 autologous and the 35 allogeneic BMT patients only two allogeneic BMT patients were weakly IgG reactive towards VLPs and 1 year after BMT this activity was lost in one of the two patients.

Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings.

Among 42 consecutive recipients of unrelated marrow were 39 HLA-A, -B, -DR identical, matched unrelated donors (MUD) and three with one HLA antigen mismatch. The majority were genomically typed for DRB, DQA, DQB and DPB. The recipients of MUD marrow were compared with 39 recipients of marrow from HLA-identical siblings with similar diagnoses, disease status and age. Each group included 24 patients with hematological malignancies, 6 with severe aplastic anemia and 9 inherited disorders. Immunosuppression consisted of anti-thymocyte globulin (ATG; pre-BMT mainly to recipients of unrelated marrow), CsA and four doses of MTX. Grade I acute GVHD was treated with prednisolone 2 mg/kg. In a comparison of MUD marrow recipients and HLA-identical siblings 34 of 39 and 36 of 39 of the patients engrafted, respectively. Recipients of MUD marrow and HLA-identical siblings achieved 0.2 x 10(9) WBC/l on day 16 (median) and 14, respectively (P = 0.03). Furthermore, the recipients of MUD marrow needed more platelet transfusions (P = 0.04). The incidence of acute GVHD grade II-III was 15% in the MUD marrow recipients compared with 11% among the HLA-identical siblings. The 2-4 year cumulative incidence of chronic GVHD was 29% and 22% in the two groups, respectively. The overall 2-year survival was 59 and 78%, respectively. Among patients with CML in chronic phase or accelerated phase (n = 26), 2-year relapse-free survival was 79% in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Human papilloma virus (HPV) and p53 immunostaining in advanced tonsillar carcinoma--relation to radiotherapy response and survival.

BACKGROUND: Human papilloma virus (HPV), which is frequently present in tonsillar carcinoma seems to be a prognostically favourable factor for patient survival and also for low risk of relapse. Since HPV may abrogate the function of wild type p53 and hence influence radiosensitivity we attempted to analyse if HPV and p53 status in tonsillar carcinoma affected tumour response to radiotherapy (RT) and patient survival. MATERIALS AND METHODS: Pre-treatment primary tonsillar carcinoma specimens were obtained retrospectively from 40 patients, 21 complete responders (CR) and 19 non-complete responders (non-CR) of which 38/40 were stage III and IV tumours. The paraffin-embedded biopsies were analysed for presence of HPV DNA, by general and type specific PCR, and for p53 overexpression by immunohistochemical staining with the murine Mab DO-1. RESULTS: It was possible to analyse HPV in 34 and p53 in 39 patients. Presence of HPV DNA (HPV+) and p53 immunostaining (p53+) were not correlated with response to RT, since 8/18 CR patients and 6/16 non-CR patients were HPV+ and 11/21 CR patients and 8/18 non-CR patients were p53+. A tendency towards a survival benefit in patients with HPV+ tumours was observed and this tendency was significant for patients with stage IV HPV + tumours (p = .0431), and in particular HPV+/p53- cancers (p = .0195). A difference in survival between patients with p53+ cancer as compared to patients with p53- lesions was not demonstrated. In conclusion, although presence of HPV and p53 immunoreactivity in tonsillar carcinoma could not be related to RT response, determination of HPV and p53 status may still prove useful as predictive/prognostic markers.

Involvement of aberrant p53 expression and human papillomavirus in carcinoma of the head, neck and esophagus.

Biopsies from 34 patients with cancer of the head, neck or esophagus, 2 laryngeal papillomas, and 2 normal tonsils were analysed for human papillomavirus (HPV), Epstein Barr virus (EBV) genomes and mutated or elevated levels of p53. In 4 biopsies p53 was also analysed by DNA sequencing. HPV type 31 was found in one laryngeal cancer with normal p53 and HPV type 16 in two tonsil cancers with aberrant p53 expression. EBV was detected by PCR in 11 biopsies, but in situ hybridisation and immunohistochemistry, did not confirm this finding. Aberrant p53 expression was observed in approximately half of the tumours. These results support the involvement of both aberrant p53 expression and HPV in the aetiology of squamous cell carcinoma of the head and neck.

Studies on the possible chemical, immunochemical and morphological differences at the cell surfaces of immunosensitive and immunoresistant, Moloney virus-induced, lymphoma cell-lines.

Comparison was made of several cell-surface parameters in the immunosensitive, Moloney virus-induced, mouse lymphoma, YAC, and its immunoresistant variant, YACIR. The characteristics of the two cell lines appeared to be similar by most of the criteria employed. The poly(acrylamide)-gel electrophoresis (with sodium dodecyl sulfate) patterns, after staining with Coomassie Brilliant Blue, of detergent-solubilized materials, appeared to be identical. After elution from a gel filtration column, no major differences were observed in the protein profiles of material cleaved from viable cells by proteolysis. Scanning and transmission electron microscopy revealed no major differences between the YAC and YACIR cells. The concentration of the lectins, Ricinus communis agglutinin, concanavalin A, wheat-germ agglutinin, and Solanum tuberosum (potato) agglutinin, required to agglutinate viable cells of the two lines were not significantly different. Neither cell was agglutinated by the lectins from Dolichos biflorus or Vicia graminea. Significant differences were, however, observed in the concentrations of lectin from Arachis hypogaea (peanut) needed to agglutinate the two cells. Although similar amounts (184-188 micrograms/10(9) cells) of sialic acid were released from viable cells by neuraminidase (V. cholerae), striking differences were observed in the composition of this material: 48% of N-glycolylneuraminic acid for YAC and 15% for YACIR. The remainder was N-acetylneuraminic acid for each cell line.

Persistence of polyomavirus in adult SCID C.B-17 mice.

C.B-17 mice with the Severe Combined Immune Deficiency (SCID) mutation were infected with the naturally occurring murine polyomavirus. Using the Polymerase Chain Reaction (PCR) technique, persistence of polyomavirus was followed in different tissues of the mice between 24 hours and 2 months post infection (p.i.). Viral DNA appeared by 3-5 days and was detected in all studied organs by 3 weeks p.i. From 4 weeks to 2 months p.i. viral DNA was present at high levels in all studied organs in all of the animals. As controls normal C.B-17 and A/Sn mice were used. Viral DNA appeared by 2-4 days. The infection reached a peak around 1 week p.i. This was followed by a clearing stage and viral DNA was no longer detectable by 4-5 weeks p.i. Most organs studied with PCR were also examined histologically, but no lesions were observed. Consequently persistence and organ distribution of polyomavirus in adult SCID mice differs greatly from that in normal adult mice.

Adult X-linked immunodeficiency (XID) mice, IGM-/- single knockout and IGM-/- CD8-/- double knockout mice do not clear polyomavirus infection.

The importance of antibodies for elimination of polyomavirus infection and the prevention of virus induced oncogenesis was studied, X-linked immunodeficiency (XID) mice, IgM-/- single knockout and IgMI-/- CD8-/- double knockout mice, all defective in antibody production, and normal control mice were infected with polyomavirus as adults. The mice were followed for presence of polyoma DNA with a polyoma specific polymerase chain reaction (PCR) over 6 weeks post infection (p.i.), a time point at which polyomavirus DNA is no longer detected in normal adult infected mice. As expected, virus DNA was not detected in normal mice 6 weeks p.i. In both IgM-/- single knockout and IgM-/- CD8-/- double knockout mice a disseminated infection was still observed by 6 weeks p.i. and the latter group of mice succumbed around two months p.i. In XID mice, only one third of the mice were still positive for viral DNA 6 weeks p.i. No polyomavirus induced tumors were observed in any of the mice during the 2-4 month observation period.

Susceptibility to polyoma virus tumorigenesis in X-linked immunodeficient (XID) and B-cell deficient (microMT) mice is not increased.

Polyoma virus induced tumorigenesis is controlled by T-cells, while B-cells clear virus infection. In order to study if T-cells can override the tumorigenic effect of a long term disseminated viral infection, the tumorigenicity and persistence of polyoma virus in antibody deficient adult and newborn infected X-linked immunodeficient (XID) and microMT mice was followed. In newborn infected XID and CBA control mice (sensitive to tumorigenesis), the frequency of tumor development was similar, and viral DNA was persistent at least 10 months p.i. In polyoma-infected newborn and adult microMT, and control C57BL/6 mice (resistant to tumorigenesis) as well as in adult XID and CBA control mice, no polyoma tumors were observed. Nevertheless, viral DNA was detected in most tissues in all microMT mice throughout the 5-7 month observation period, whereas in the remaining groups of mice persistent viral infection was limited or not detected. We suggest that the tumorigenic potential of an extensive persistent polyoma virus infection can be overcome as long as a functional T-cell system is present.