Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However many aspects regarding monocyte brain recruitment in HIV infection remain undefined. Limited evidence suggests monocytes become HIV or simian immunodeficiency virus (SIV)-infected in bone marrow prior to their release into the peripheral cell pool and trafficking to the brain. Here, we would like to examine bone marrow production of monocytes during acute inflammation and functionality of newly emerging monocytes in the rhesus macaque animal model for Acquired Immunodeficiency Syndrome (AIDS). We hypothesize that SIV infection triggers increased bone marrow output and emigration of monocytes into the peripheral cell pool. Newly released monocytes exhibit high capacity for neuroinvasion and production of proinflammatory mediators. We will test our hypothesis with the following specific aims.
Specific Aim#1 : Define kinetics and magnitude of bone marrow monocyte output in acute SIV infection. This will be addressed by depleting peripheral blood monocytes using clodronate liposomes which target phagocytic cells circulating in peripheral blood when administered intravenously. Upon treatment interruption, frequency of blood monocytes and dynamics of monocyte recovery in the peripheral cell pool will be determined in acute SIV infection and contrasted with the uninfected state.
Specific Aim#2 is directed towards examining phenotype and function of newly released monocytes. Following depletion, newly released peripheral blood monocytes will be characterized phenotypically and functionally, based on presence of activation markers, migratory parameters and capacity to produce proinflammatory mediators and monocyte chemoattractants such as CCL2/MCP-1 with a proposed role as a brain chemokine trigger.
Specific Aim#3 : Determine if depletion of peripheral blood monocytes prevents viral brain entry and neuroinflammation. The goal of this aim is to examine if monocyte depletion during acute SIVmac251 infection prevents virus import into the Central Nervous System (CNS) and monocytes'role as `Trojan Horse'for virus brain entry. Significance: The dynamics of monocyte emigration from bone marrow and entry into the peripheral cell pool as well as possible brain tissue-specific trafficking mechanisms are only poorly defined. Determining the dynamics of monocyte production, characteristics of newly released monocytes in peripheral blood and their capacity for early brain infiltration with import into the CNS in SIV infection could lead to novel drug targeting and treatment options to inhibit acute and chronic neuroinflammation by targeting specific monocyte subsets or their migratory signals.
The overall goal of this proposed study is to characterize the role of monocytes as `Trojan Horse'for viral brain entry in an animal model for acquired immunodeficiency virus syndrome (AIDS). The specific objective is to examine possible altered bone marrow functions and monocyte output during acute infection and how monocytes, once emerged into the peripheral blood pool, migrate onward into the Central Nervous System. Defining the characteristics of newly released monocytes in the peripheral blood pool and their capacity for early brain infiltration could lead to novel drug targeting and treatment options that inhibit acute and chronic neuroinflammation by targeting specific monocyte subsets or their migratory signals.
