HIV-driven B cell activation: role in the genesis of AIDS-related lymphoma

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Untreated HIV infection results in not only in the progressive loss of T cell immune function, but also in chronic polyclonal B cell activation. The risk for developing B cell non-Hodgkin's lymphoma also is greatly elevated in HIV+ persons. Virtually all AIDS-related lymphomas (ARL) are of B cell origin. HIV infection-associated B cell hyperactivation is believed to play a central role in the genesis of ARL, as B cell activation involves two molecular processes that can create the seminal molecular lesions seen in ARL: 1) immunoglobulin heavy chain gene (IgH) class switch recombination (CSR), a process that involves double-strand DNA breaks and recombination, and 2) somatic hypermutation (SHM), DNA hypermutation of the variable region of antibody genes. Errors in IgH CSR and SHM can lead directly to oncogene mutations and/or translocations that result in ARL. IgH CSR and SHM are both mediated by activation-induced cytidine deaminase (AICDA), a member of the APOBEC family. In our prior work, we saw that PBMC B cell AICDA expression was elevated for several years preceding the diagnosis of ARL, as were serum levels of B cell stimulatory cytokines. We also found that HIV virions carrying CD40 ligand (CD40L), a T cell-produced B cell stimulatory molecule, can drive B cell activation and AICDA expression. Given that HIV can potently induce B cell activation via host cell- encoded stimulatory molecules incorporated into virions, and that B cell activation can contribute to the development of ARL, it is important to better define the role of such virion-associated stimulatory molecules in driving B cell activation With this in mind, the specific aims of this study are to: 1) define the ability of CD40L+ HIV to promote oncogenic events in B cells, 2) define the expression of CD40L on HIV virions in vivo, throughout the course of HIV disease, and 3) determine if the development of ARL is associated with elevated expression of CD40L or other B cell-stimulatory molecules on HIV virions from plasma, as well as with a gene expression pattern in circulating T cells that is characteristic of TFH/TH17 cells, elevated serum levels of B cell- stimulatory cytokines, and/or, elevated plasma levels of EBV and/or KSHV DNA. By better defining the association of CD40L+ HIV and ARL we hope to elucidate the pathogenesis of these cancers, providing information that will inform future work on risk assessment and early detection, and on the development of therapeutics.