Association between simian virus 40 and non-Hodgkin lymphoma

Summary

Background

Non-Hodgkin lymphoma has increased in frequency over the past 30 years, and is a common cancer in HIV-1-infected patients. Although no definite risk factors have emerged, a viral cause has been postulated. Polyomaviruses are known to infect human beings and to induce tumours in laboratory animals. We aimed to identify which one of the three polyomaviruses able to infect human beings (simian virus 40 [SV40], JC virus, and BK virus) was associated with non-Hodgkin lymphoma.

Methods

We analysed systemic non-Hodgkin lymphoma from 76 HIV-1-infected and 78 HIV-1-uninfected patients, and non-malignant lymphoid samples from 79 HIV-1-positive and 107 HIV-1-negative patients without tumours; 54 colon and breast carcinoma samples served as cancer controls. We used PCR followed by Southern blot hybridisation and DNA sequence analysis to detect DNAs of polyomaviruses and herpesviruses.

Findings

Polyomavirus T antigen sequences, all of which were SV40-specific, were detected in 64 (42%) of 154 non-Hodgkin lymphomas, none of 186 non-malignant lymphoid samples, and none of 54 control cancers. This difference was similar for HIV-1-infected patients and HIV-1-uninfected patients alike. Few tumours were positive for both SV40 and Epstein-Barr virus. Human herpesvirus type 8 was not detected. SV40 sequences were found most frequently in diffuse large B-cell and follicular-type lymphomas.

Interpretation

SV40 is significantly associated with some types of non-Hodgkin lymphoma. These results add lymphomas to the types of human cancers associated with SV40.

Introduction

Non-Hodgkin lymphoma comprises a biologically diverse group of haematological malignancies with clinical courses ranging from indolent to highly aggressive. During the past 30 years, the reported incidence and death rate of the disease have increased strikingly, nearly doubling since 1970.¹ About 55 000 new cases of non-Hodgkin lymphoma are estimated to be diagnosed annually in the USA,¹ and deaths related to the disorder are ranked fourth and fifth among all cancer deaths in women and men, respectively. Although the reasons for the increase in incidence are not fully understood, a substantial number of cases of non-Hodgkin lymphoma are linked to the HIV-1 epidemic. Indeed, non-Hodgkin lymphoma is a common malignancy in HIV-1-infected patients and the incidence can be up to 300 times higher than in HIV-1-negative individuals.¹

No obvious risk factors have emerged for non-Hodgkin lymphoma in the general population, but a viral cause has been postulated.² Some cases of non-Hodgkin lymphoma in HIV-1-infected patients have been attributed to deficient immune surveillance of oncogenic herpesviruses, such as Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8), or perhaps to chronic antigenic stimulation and defective immune regulation.³ EBV is suspected of having a major role in primary central-nervous-system non-Hodgkin lymphoma in HIV-1-infected patients, since most of those tumours contain EBV DNA, but it is detected less frequently (<40%) in systemic non-Hodgkin lymphoma in HIV-1-infected patients.1, 2, 3 EBV is found even less commonly in non-Hodgkin lymphoma from HIV-1-negative patients. HHV-8 is specifically associated with multicentric Castleman's disease and primary effusion lymphoma, which often occurs in a setting of profound immunosuppression.2, 4

Because EBV and HHV-8 are absent from many cases of non-Hodgkin lymphoma, other viral agents should be considered as possible causes. The small DNA-containing polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus) are known to infect human beings, to have oncogenic potential, and to be associated with some human cancers.2, 5, 6 SV40 DNA sequences have been found repeatedly in some brain and bone cancers and mesotheliomas.⁵ Polyomaviruses typically establish subclinical and persisting infections in their natural host, with persistence or latency in several organs, including kidney, brain, and spleen.² Studies have identified SV40, JC virus, and BK virus DNA sequences in B lymphocytes from HIV-1-infected and HIV-1-uninfected patients, suggesting that polyomaviruses are lymphotropic in man.7, 8, 9 Polyomaviruses are known to induce tumour formation in animals, including the production of B-cell lymphomas by SV40.¹⁰ The major types of tumours induced by SV40 in laboratory animals are the same as the human cancers found to contain SV40 DNA, with the exception of lymphomas.⁵ In animals, oncogenesis is mediated by the polyomavirus large tumour (T) antigen.2, 5, 6 The large T antigen is a multifunctional protein that stimulates host cells to enter S phase and is required for initiation of viral DNA synthesis. Fundamental to the effects of T antigen on host cells is binding to cellular tumour-suppressor proteins p53 and members of the pRB family.2, 5, 6

Studies have reported the detection of SV40 DNA sequences in non-Hodgkin lymphoma from HIV-1-infected and HIV-1-uninfected patients,9, 11, 12 and the amplification of JC virus DNA sequences from systemic non-Hodgkin lymphoma of HIV-1-infected children.¹³ These findings suggest a possible role for polyomaviruses in lymphoproliferative disorders, but the small size of the study populations, the lack of screens for other tumour viruses, and the limited confirmation of identity of the viral sequences detected made conclusion of whether polyomaviruses were definitely associated with non-Hodgkin lymphoma difficult. We aimed to determine the frequency of detection of polyomavirus T antigen DNA sequences in non-Hodgkin lymphoma among HIV-1-infected and HIV-1-uninfected patients, to identify which one of the three polyomaviruses able to infect humans (SV40, JC virus, and BK virus) was associated with non-Hodgkin lymphoma in adult patients, and to establish clinical correlations between the presence of viral sequences and non-Hodgkin lymphoma among HIV-1-infected and HIV-1-uninfected patients. The HIV-1-infected population was included in this study because of their high incidence of non-Hodgkin lymphoma and because immunocompromised individuals are known to be at risk of development of virus-mediated neoplasms.²