Measles remains a major cause of morbidity and mortality worldwide due to problems with delivery, acceptance and timing of measles immunization. An additional contributor to the continued failure of measles control may be the epidemic of human immunodeficiency virus (HIV) in developing countries, particularly sub-Saharan Africa, where many of the measles deaths occur. The primary complications of measles are pneumonia, otitis media, diarrhea and post-infectious encephalomyelitis and the effect of measles virus (MV) on the immune system is important in the development of these complications. Delayed type hypersensitivity skin test responses, natural killer cell activity and mitogen-induced proliferative responses are depressed and plasma IgE is increased for weeks after infection. At the same time, the immune response is effective in clearing virus from tissue and in establishing lifelong immunity to reinfection. Our studies of measles in the US and Peru have determined: (i) that monocytes, epithelial cells and endothelial cells are the primary sites of MV replication in vivo; (ii) that there is immune system activation during the period of """"""""immune suppression""""""""; and (iii) that type 2 cytokines are the predominant T cell cytokines expressed late in the response to MV. In vitro studies have shown that MV interaction with CD46 suppresses production of IL-12 by macrophages and that MV infection of B cells synergizes with IL-4 to induce IgE class switching. Recent studies in Zambian children have shown that concurrent HIV infection slows clearance of MV, that many children have baseline skewing of cytokine responses toward production of IL-5, and that measles transiently, but profoundly, suppresses HIV replication. To define the role of host immune responses during measles and the effect of concurrent HIV infection on these responses, we propose the fol]owing specific aims: 1. To determine the effects of MV infection on antigen presenting cells in vivo and in vitro and the consequences of these effects for the immune response. 2. To determine the role of CD8 T cells in MV clearance and the effect of concurrent HIV infection on this role. 3. To determine the roles of different CD4 and CD8 T cell populations in production of cytokines at various times during measles and the effect of concurrent HIV infection on these roles.
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