Caroline Alfieri

Epstein-Barr virus (EBV) has been associated with serious or fatal lymphoproliferative disease in immunocompromised patients. EBV nuclear protein 2 and latent membrane protein are characteristically expressed in B lymphocytes proliferating in vitro in response to growth transformation by EBV. These two proteins are thought to be effectors of lymphocyte growth since they increase the expression of B-lymphocyte activation (CD23) and cell-adhesion (LFA 3 and ICAM 1) molecules in vitro. Using monoclonal antibody-immune microscopy, we have demonstrated that these two EBV proteins and their associated B-lymphocyte activation or adhesion molecules are expressed in the infiltrating B lymphocytes in immunocompromised patients with EBV lymphoproliferative disease. These monoclonal antibodies should be useful in the early diagnosis of EBV lymphoproliferative disease and in distinguishing it from other B-lymphocyte cancers associated with EBV, such as Burkitt's lymphoma. The finding of EBV nuclear protein 2 and latent membrane protein and their associated activation or adhesion molecules provides a further pathophysiologic link between EBV and the proliferation of B lymphocytes in immunocompromised patients.

The Epstein-Barr virus (EBV) is known to cause posttransplant lymphoproliferative disease (PTLD) in immunosuppressed transplant patients. The results of this pilot study showed that all EBV- patients pretransplant experienced primary EBV infection within the first 3 months after transplant surgery. Virtually all of these patients had a higher burden of EBV-infected cells in their peripheral blood (PB) after infection by EBV than did the EBV+ pretransplant group when tested at the same intervals posttransplant. Salivary EBV titers also increased in most patients, but the difference between the two groups was statistically significant only at 12 months, whereupon EBV+ patients showed higher titers compared with EBV- (alpha < 0.053). Also, polymerase chain reaction amplification followed by Southern blotting was performed to detect EBV sequences in PB mononuclear cells. This technique allowed confirmation of the blood culture results and constituted a faster alternative compared with the culture assay. The highest increase in the number of EBV-infected lymphocytes at 3 months posttransplant obtained from PB was seen in a patient who developed fatal PTLD and in another with protracted infectious mononucleosis. Thus, the number of EBV-infected cells in PB was found to correlate positively with risk of development of PTLD at 3 months posttransplant in our group of pediatric transplant patients. This study showed that quantitative lymphocyte culture of PB was an accurate index of immunosuppression and a reliable method for assessing the risk of PTLD development.

Transplant patients are at particular risk for developing post-transplant lymphoproliferative disease (PTLD) following administration of immunosuppressive therapy. In many cases the PTLD lesions express Epstein-Barr virus (EBV) latent and lytic genes as well as elevated levels of host cytokines. An outline of the potential contributions of EBV, host cytokines and T cells, and the immunosuppressive cyclosporine A, tacrolimus, and anti-CD3 antibody in the mechanism and pathogenesis of this disease is presented and discussed.

Human immunodeficiency virus (HIV)-positive individuals express elevated levels of interleukin-8 (IL-8), which is believed to be responsible for some of the clinical manifestations occurring during AIDS. We report here that virion-derived HIV type 1 (HIV-1) protein R (Vpr) increased IL-8 expression in primary T cells and macrophages, as well as in the T-cell line Jurkat, the monocytic cell line U937, and the epithelial cell line A549. Vpr appeared to increase IL-8 expression and IL-8 promoter activity by activating transcription factors NF-kappaB and NF-IL-6. Elevated Vpr was also shown to increase transcription of the NF-kappaB and NF-IL-6 enhancer-containing viral promoters for HIV, cytomegalovirus, and simian virus 40, as well as increase the expression of IL-6 and IL-10 in primary macrophages and in A549 cells, tumor necrosis factor alpha expression in primary T cells, and IL-6 and gamma interferon expression in U937 cells. These results suggest a new role for Vpr in the pathogenesis of HIV infection, namely, the activation of transcription factors NF-IL-6 and NF-kappaB.