We propose a multi-step model linking the development of HIV dementia with systemic events which occur with the onset of AIDS, and subsequently. We theorize that the Initial critical step is an increase in the trafficking of blood monocytes into the brain parenchyma, and that this is facilitated by the activation of these cells prior to their exit from bone marrow (BM). Specifically, we suggest that events related to either HIV infection within BM, and/or the generalized immune activation which accompanies AIDS, lead to increased production of macrophage colony stimulating factor (M-CSF) within BM which, in turn, leads to induction of CD16 expression on a greater number of the exiting monocytes. Being activated, these cells are primed for transendothelial migration, and hence, can more readily cross the blood-brain barrier. We propose that macrophages themselves, uninfected as well as HIV-infected, are the primary instigators of the neuropathological processes leading to HIV dementia, and that HIV infection within the brain plays a lesser role. Once within the brain parenchyma, the monocytes can produce, as well as elicit from other cells, neurotoxins such as proinflammatory cytokines. Considerable evidence supports this possible outcome. To link the proposed increase in monocyte trafficking into brain with post-entry events and dementia, we propose to characterize the (CD14+) perivascular macrophage population in AIDS brains, with respect to CD16 and HIV expression, and 0-amyloid precursor protein (0-APP)-deposition, the laner being a marker of axonal injury. Based on reports that the alipoprotein E4 allele (apo E4), a known risk factor for Alzheimer's dementia, is also associated with higher levels of circulating CD16+ monocytes, as well as HIV dementia, we will examine this enotype in conjunction with CD16+ monocytes and HIV-associated cognitive impairment. To test our model, we will characterize blood monocytes from HIV-infected patients with and without dementia, followed longitudinally, for activation, proliferation, HIV infection, and surface expression of P-APP. M-CSF levels in cerebrospinal fluid, serum and brain and BM tissues will be determined. Immunostaining will be used to evaluate brain and bone marrow sections for the abundance of CD14, CD16 and HIV expression. To study monocyte trafficking from BM to brain, phylogenetic analyses will be performed using HIV gpl 60 species cloned from uncultured tissues as """"""""tracers."""""""" PCR-based genotyping for apo E will be included. If valid, our model could lead to new approaches for the prevention and treatment of HIV dementia.
