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.
| McAllister, Shane C; Hansen, Scott G; Messaoudi, Ilhem et al. (2005) Increased efficiency of phorbol ester-induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus during S phase. J Virol 79:2626-30 |
| Henderson, Winnie W; Ruhl, Rebecca; Lewis, Paul et al. (2004) Human immunodeficiency virus (HIV) type 1 Vpu induces the expression of CD40 in endothelial cells and regulates HIV-induced adhesion of B-lymphoma cells. J Virol 78:4408-20 |
