Mechanisms of HIV Entry into the CNS: Increased Sensitivity of HIV Infected CD14+CD16+ Monocytes to CCL2 and Key Roles of CCR2, JAM-A, and ALCAM in Diapedesis

Abstract

As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14+CD16+ monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14+CD16+ monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14+CD16+ monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14+ cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14+CD16+ monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14+CD16+ monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14+CD16+ monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.

Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier

“…Our data suggest that ALCAM plays a role in HAM/TSP pathogenesis similar to its role in neuroAIDS. Indeed, in neuroAIDS, ALCAM levels are not altered on the BBB endothelium (18), HIV infection increases ALCAM expression on monocytes (20), and ALCAM blockade by neutralizing antibodies reduces HIV-infected monocyte extravasation in in vitro BBB models (19,20).…”

“…We tested the impact of an anti-ALCAM blocking antibody (used in previous studies [17,19,20]) on the transmigration of T cell lines through a monolayer of human cerebral microvascular endothelial hCMEC/D3 cells cultured on a Transwell device to determine if ALCAM plays a role in the migration of HTLV-1-infected lymphocytes across the BBB. These cells have been extensively used as a relevant in vitro model for the human BBB endothelium (37).…”

“…Leukocytes express both ALCAM and CD6, which can interact with endothelial ALCAM. ALCAM has been implicated in monocyte interaction with the BBB and monocyte migration into the CNS during human immunodeficiency virus type 1 (HIV-1) infection (18)(19)(20).…”

Splenic Damage during SIV Infection

“…79,80 In uninfected macaques, only 14.1% AE 0.4% of splenic monocytes expressed CD16 ( Figure 4B). This was significantly increased during SIV infection as early as 7 dpi, and peaked at 21 dpi where 88.4% AE 2.0% of cells expressed CD16.…”

Dual role of ALCAM in neuroinflammation and blood–brain barrier homeostasis

“…Furthermore, we have previously demonstrated that physical hindrance of ALCAM during active EAE, using anti-ALCAM blocking antibodies, delays the progression and reduces the severity of the disease, while also partially preventing the infiltration of leukocytes in the CNS (11). In addition, several groups have demonstrated the involvement of ALCAM in leukocyte transmigration across human BBB-ECs or MBECs (11,12,(38)(39)(40)(41).…”