Initial neuroinvasion is likely mediated by human immunodeficiency virus (HlV)-infected monocytes which cross the blood-brain barrier (BBB) during acute infection and introduce virus into the central nervous system (CNS), ultimately leading to neurological complications and HIV-associated dementia in a third of all HIV+ patients. Monocyte CNS invasion is accompanied by inflammation and brain-specific immune responses at this sequestered site. Inflammatory processes, altered adhesion marker and chemokine expression lead to the destruction of the BBB and promote continued leukocyte trafficking into the CNS which may culminate in characteristic brain lesions and HIV-associated dementia (HAD). The rhesus macaque AIDS model is the best available animal model to study neurological complications and the development of neuro-AIDS in primates. However thus far, in vivo leukocyte trafficking studies in primates have not been feasible. Our group has overcome this technology gap and successfully conducted in vivo leukocyte trafficking studies in rhesus macaques, the first laboratory to conduct such studies in primates [1]. Importantly, we recently identified CNS-infiltrating, fluorescein dye-labeled monocytes in the cerebrum and choroid plexus of simian immunodeficiency virus (SIV)mac251-infected macaques within 48-hours post autologous leukocyte transfer (see preliminary data), providing us the unique opportunity to explore key open questions in the field of neuro-AIDS research, relating to tissue source and mechanisms of in vivo monocyte trafficking into the brain. Accordingly, the specific objectives of this study are to define the tissue origin, spatial and temporal dynamics of in vivo monocyte homing and possible unique migratory characteristics of CNS-infiltrating monocytes. We hypothesize that monocytes in acutely SIV-infected macaques are released from bone marrow as a consequence of cell activation and reduced chemokine-mediated tissue retention. Furthermore, we propose that their release into peripheral blood facilitates the responsiveness to brain chemokine signals and CNS infiltration in a tissue-specific manner. This triggers virus entry into the CNS and neuroinflammation, thereby setting the stage for neurological disease and AIDS-associated dementia.
Specific Aim 1. Identify the tissue origin and characterize brain-infiltrating monocytes in acute SIV infection Specific Aim 2. Define the role of sialoadhesin, CCL2. CX3CL1 and CXCL12 as monocyte migratory triggers ? ?
| Clay, Candice C; Rodrigues, Denise S; Ho, Yan S et al. (2007) Neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection. J Virol 81:12040-8 |
