HIV associated neurocognitive disorders (HAND) encompass a spectrum of cognitive deficits that affect 40-70% of HIV-infected individuals, despite antiretroviral therapy. Monocytes are among the first cells infected by HIV and are critical mediators of HAND as they facilitate viral seeding of the central nervous system (CNS) upon their transmigration across the blood brain barrier (BBB). Monocyte subpopulations exist with differing levels of maturation and functions. Monocytes that express CD14, the LPS receptor, and CD16, the Fcylll receptor, are a mature population of cells that are highly susceptible to HIV. While CD14+CD16+ monazites are believed to mediate the neuropathogenesis of HIV, little is known about the mechanisms that contribute to their diapedesis across the BBB. As the CD14+CD16 + monocyte represents a small percentage of monocytes in healthy individuals, we developed a tissue culture model to enrich for this population. We found that there was a selective transmigration of CD14+CD16 + monocytes across our BBB model, with little migration of other monocyte populations. HIV infection resulted in the increased transmigration of CD14 +CD16+ monocytes in response to CCL2 relative to uninfected cells, which was due to increased CCR2 and a heightened sensitivity to the chemokine. The junctional proteins JAM-A and ALCAM were also critical for this transmigration as antibody blockade reduced the number of migrating monocytes. These CD14+CD16+ monocytes were present in significantly greater numbers in HIV-infected people, despite viral suppression, in contrast to individuals without HIV. CCR2 was increased on CD14+CD16+ monocytes in HIV-infected individuals with HAND compared to those with normal cognition and was predictive of fluctuations in cognitive impairment upon longitudinal study. ALCAM and JAM-A were increased on CD14+CD16 + monocytes in those with HIV compared to HIV seronegative people. Blocking antibodies to ALCAM and JAM-A inhibited the transmigration of CD14 +CD16+ monocytes, but not of T cells, suggesting their importance in specifically facilitating monocyte transmigration across the BBB. Our findings indicate therapeutic strategies to monitor HAND, and that may decrease the entry of CD14+CD16+ monocytes into the CNS of HIV-infected individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
|Advisor:||Berman, Joan W.|
|School Location:||United States -- New York|
|Source:||DAI-B 75/08(E), Dissertation Abstracts International|
|Keywords:||Adhesion Molecole, Central Nervous System, Chemokine, Cognitive Deficits, HIV, Monocyte|
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