description) AIDS patients have an unusually high incidence of aggressive B cell non-Hodgkin's lymphomas (AIDS-NHL) that frequently involve extranodal sites, in particular the gut, liver brain and bone marrow. While neoplastic B cells are not directly infected with human immunodeficiency virus type 1 (HIV), interaction with HIV-infected non-B accessory cells at extranodal sites may contribute to localization and development of malignant clones. This group have previously shown that bone marrow microvascular endothelial cells (MVEC) are a natural target for HIV in vivo and in vitro. Since MVEC interact with B cells during hematopoiesis as well as during leucocyte trafficking and extravasation, they hypothesize that HIV infection of MVEC may influence neoplastic B cell attachment and growth and facilitate extranodal lymphoma development: Using a novel MVEC-enriched stromal culture system, they have shown that HIV infection of stromal cultures from seronegative lymphoma patients induces the sustained outgrowth of EBV-negative B lymphoma cells which are dependent on stroma for growth. They have also demonstrated that the only cellular component infected by HIV in these cultures are MVEC, and that purified populations of infected but not uninfected brain MVEC are equally supportive of neoplastic B cell growth. These data suggest that HIV infection of permissive MVEC alters their ability to induce and sustain malignant B cell growth. The investigators have recently identified a mechanism whereby HIV regulates MVEC-B lymphoma interactions. Specifically, CD40 expression is preferentially induced on infected MVEC allowing CD40-mediated upregulation of VCAM-1 and subsequent VCAM-1/VLA-4 mediated MVEC-B cell binding. This project will extend these results by characterizing the relative kinetics of CD40 expression and CD40-mediated VCAM-1 expression in HIV-infected MVEC. They will also identify the viral gene(s) which mediate these events using HIV deletion mutants and recombinant viral constructs containing individual viral genes. Finally, this group will characterize the signal transduction pathways through which HIV regulates CD40 expression and CD40-mediated VCAM-1 expression using a transcriptional readout system, biochemical assays for phosphorylation of signal transduction intermediates and transdominant negative mutants which block signal transduction. Identification of these mechanisms may suggest therapeutic targets to prevent development of extranodal B cell neoplasms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061928-03
Application #
6184567
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Wang, Lan-Hsiang
Project Start
1998-09-20
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$260,750
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239