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Project 2
Epidemiology of Lymphoma in HIV-infected Populations

Principal Investigator(s): Otoniel Martinez-Maza, Ph.D. (Basic); Richard F. Ambinder, M.D., Ph.D. (Clinical) Co-Investigator(s): Lisa Jacobson, Ph.D.; Michael Dean, Ph.D.; Liz Breen, Ph.D.

Non-Hodgkin's B cell lymphoma (AIDS-NHL) is seen in greatly-elevated frequency in HIV-infected people. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-NHL. In preliminary studies, elevated levels of several immune system molecules that are associated with B cell activation (IL6, IL10, sCD23, sCD27, sCD44, and IgE), were seen prior to the clinical detection of AIDS-NHL. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-NHL, suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, genetic polymorphisms in the genes encoding IL10, SDF1, and CCR5 have been seen to be associated with the development of AIDS-NHL. These findings are of great significance, since few molecular risk factors have been identified for AIDS-NHL. The proposed studies will: 1) determine if enhanced B cell stimulation (elevated serum levels of B cell-stimulatory cytokines or of immune system molecules associated with B cell activation), and/or increased in vivo EBV levels, precede the development of AIDS-NHL, 2) determine if HAART affects the pre-lymphoma expression of B cell stimulatory molecules and/or in vivo EBV levels, 3) determine if polymorphisms in the genes encoding B cell-stimulatory cytokines or cytokine receptors are associated with an elevated risk for the development of AIDS-NHL, and 4) to define a pattern of molecular markers that identify those HIV+ people who are at increased risk for the development of AIDS-NHL, and then carry out a pilot clinical study to assess treatment of such high-risk individuals with prophylactic anti-lymphoma therapy (rituximab). Determination of characteristics preceding the development of AIDS-NHL will involve a case-control study, nested within two well-characterized cohort studies (the MACS and the ALIVE study), in which serial specimens have been collected and frozen. The same nested design will be utilized to examine the association between polymorphisms in genes encoding B cell-stimulatory cytokines and cytokine receptors and the development of AIDS-NHL, using specimens from the MACS and ALIVE study, as well as from the AIDS Malignancies Consortium (AMC). These studies will add valuable new information, which could form the foundation for future studies on the pathogenesis of AIDS-NHL, and is expected to lead to new risk-assessment schemes to allow earlier and more effective clinical intervention. The proposed studies will be carried out as a collaboration between workers at UCLA (Martínez-Maza and Breen), JHU (Jacobson and Ambinder), and NCI-Frederick (Dean).


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