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Epstein-Barr virus (EBV) is implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS) lymphoma, and viral DNA is present within the malignant cells in about half of affected patients. We examined the extent to which EBV viral load is elevated in the plasma of AIDS lymphoma patients compared to AIDS patients with opportunistic infections. Sixty-one AIDS patients were studied including 35 with lymphoma (24 non-Hodgkin, six Hodgkin, and five brain lymphoma) and 26 with various opportunistic infections. In situ hybridization revealed EBV encoded RNA (EBER) expression in the malignant cells of 17/28 AIDS lymphomas (61%). In 232 serial plasma samples from 35 lymphoma patients and in 128 samples from AIDS controls, EBV viral load was assayed by quantitative-polymerase chain reaction (Q-PCR) using a TaqMan probe targeting the BamH1W sequence. EBV was detected in plasma from all 17 EBER-positive AIDS lymphoma patients, with viral loads ranging from 34 to 1,500,000 copies per ml (median 3,210). Viral load usually fell rapidly upon initiation of lymphoma therapy and remained undetectable except in two patients with persistent tumor. In 11 AIDS patients, whose lymphoma lacked EBER expression, and in 26 control patients without lymphoma, levels of EBV in plasma were usually low or undetectable (range 0-1,995 and 0-2,409, median 0 and 0, respectively). There was no association between EBV viral load and human immunodeficiency virus (HIV) load or CD4 count. In conclusion, EBV viral load shows promise as a tool to assist in diagnosis and management of EBV-related lymphoma patients.

A monoclonal antibody (Rituximab) directed against the B-cell surface antigen,

The consistent presence of the Epstein-Barr virus (EBV) genome in certain malignancies, particularly its nearly universal presence in AIDS-related central nervous system lymphomas (4, 6, 29) and nasopharyngeal carcinomas (31), suggests that EBV itself could serve as a target for the preferential killing of tumor cells using gene delivery methods. Although the use of adenovirus vectors expressing EBV-specific toxins could potentially be useful for treating EBV-positive epithelial cell tumors, EBV-associated B-cell tumors are unlikely to be susceptible to conventional adenovirus-mediated delivery. The recently identified adenovirus receptor for serogroups 2 and 5, the coxsackievirus-adenovirus receptor (CAR), is not expressed in most hematologic cell lines (19,28,44), and consequently, adenovirus delivery to most B-cell lines is extremely inefficient. Nevertheless, other advantageous aspects of recombinant adenovirus vectors (rAd), including the extremely high achievable titers and the large size (10 kb) of the gene inserts tolerated, continue to make rAd the most attractive currently available gene delivery vectors. Therefore, there has been intense interest in modifying rAd to improve their delivery into hematopoietic cell types.Bispecific antibodies (BsAb) are covalently linked antibodies with distinct specificities (40). BsAb can extend a virus's normal tropism by using specific antibodies to the virus's receptor (the fiber protein, in the case of adenovirus [41]) and an alternate cellular ligand. For example, the delivery of rAd with a FLAG epitope-modified adenovirus fiber protein to T cells was shown to be greatly enhanced when a bispecific antibody directed against the FLAG epitope and the T-cell-specific CD3 cell surface receptor (48) was used. The method has been applied to other virus-cell surface ligand systems (5,7,49).In this study, we have investigated the use of an anti-CD70-antifiber BsAb to enhance adenovirus delivery to CD70-positive B-cell lines. CD70 expression is usually limited to a small subset of highly activated B and T cells (42). In contrast, EBV-immortalized B cells (lymphoblastoid cell lines [LCLs]) routinely express CD70 (42), as do a number of EBV-positive, as well as EBV-negative, B-cell lymphomas (17,27). Expression of CD70 (which has been identified as the CD27 ligand) on T cells appears to have a physiological role in inducing CD27 ϩ B cells to proliferate and differentiate into plasma cells (2), while on B cells, CD70 seems to have a costimulatory effect upon T cells (3). Interestingly, although CD70 expression in vivo is usually limited to a few highly activated B cells and T cells, CD70 is also expressed in EBV-positive nasopharyngeal carcinomas (1, 31). Thus, CD70 expression could potentially

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