Abstract
The human immunodeficiency virus (HIV) enters the central nervous system (CNS) within a few days after primary infection, establishing viral reservoirs that persist even with combined antiretroviral therapy (cART). We show that monocytes from people living with HIV (PLWH) on suppressive cART harboring integrated HIV, viral mRNA, and/or viral proteins preferentially transmigrate across the blood-brain barrier (BBB) to CCL2 and are significantly enriched post-transmigration, and even more highly enriched posttransmigration than T cells with similar properties. Using HIV-infected ART-treated mature monocytes cultured in vitro, we recapitulate these findings and demonstrate that HIV+ CD14+ CD16+ ART-treated monocytes also preferentially transmigrate. Cenicriviroc and anti-JAM-A and anti-ALCAM antibodies significantly and preferentially reduce/block transmigration of HIV+ CD14+ CD16+ ART-treated monocytes. These findings highlight the importance of monocytes in CNS HIV reservoirs and suggest targets to eliminate their formation and reseeding.IMPORTANCE We characterized mechanisms of CNS viral reservoir establishment/replenishment using peripheral blood mononuclear cells (PBMC) of PLWH on cART and propose therapeutic targets to reduce/block selective entry of cells harboring HIV (HIV+) into the CNS. Using DNA/RNAscope, we show that CD14+ CD16+ monocytes with integrated HIV, transcriptionally active, and/or with active viral replication from PBMC of PLWH prescribed cART and virally suppressed, selectively transmigrate across a human BBB model. This is the first study to our knowledge demonstrating that monocytes from PLWH with HIV disease for approximately 22 years and with long-term documented suppression can still carry virus into the CNS that has potential to be reactivated and infectious. This selective entry into the CNS-and likely other tissues-indicates a mechanism of reservoir formation/reseeding in the cART era. Using blocking studies, we propose CCR2, JAM-A, and ALCAM as targets on HIV+ CD14+ CD16+ monocytes to reduce and/or prevent CNS reservoir replenishment and to treat HAND and other HIV-associated comorbidities.
Highlights
IMPORTANCE We characterized mechanisms of central nervous system (CNS) viral reservoir establishment/ replenishment using peripheral blood mononuclear cells (PBMC) of people living with HIV (PLWH) on combination antiretroviral therapy (cART) and propose therapeutic targets to reduce/block selective entry of cells harboring Human immunodeficiency virus (HIV) (HIV1) into the CNS
We previously demonstrated HIV1 CD141 CD161 monocytes, matured and infected in vitro, preferentially transmigrate across the blood-brain barrier (BBB) to CCL2 compared to HIVexp CD141 CD161 monocytes and that this selective advantage is facilitated by increased CCR2, the only known CCL2 receptor on monocytes, and the junctional proteins JAM-A and ALCAM [28]
We demonstrate that HIV1 PBMC transmigrate preferentially to CCL2 compared to HIVexp PBMC
Summary
IMPORTANCE We characterized mechanisms of CNS viral reservoir establishment/ replenishment using peripheral blood mononuclear cells (PBMC) of PLWH on cART and propose therapeutic targets to reduce/block selective entry of cells harboring HIV (HIV1) into the CNS. Using DNA/RNAscope, we show that CD141 CD161 monocytes with integrated HIV, transcriptionally active, and/or with active viral replication from PBMC of PLWH prescribed cART and virally suppressed, selectively transmigrate across a human BBB model This is the first study to our knowledge demonstrating that monocytes from PLWH with HIV disease for approximately 22 years and with long-term documented suppression can still carry virus into the CNS that has potential to be reactivated and infectious. HIV-infected CNS cells produce host and viral factors, such as Tat and Nef, and activate other CNS cells, leading to the release of neurotoxic mediators and cytokines, resulting in low-level chronic neuroinflammation and neuronal damage [14, 15, 25,26,27] This chronic neuroinflammatory environment persists despite cART, mediating recruitment of additional uninfected and HIV-infected cells, contributing to replenishment of CNS viral reservoirs, and possibly enabling persistence of HAND. We previously demonstrated HIV1 CD141 CD161 monocytes, matured and infected in vitro, preferentially transmigrate across the BBB to CCL2 compared to HIVexp CD141 CD161 monocytes and that this selective advantage is facilitated by increased CCR2, the only known CCL2 receptor on monocytes, and the junctional proteins JAM-A and ALCAM [28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
