The meningeal lymphatic system: a route for HIV brain migration?

Abstract

Two innovative studies recently identified functional lymphatic structures in the meninges that may influence the development of HIV-associated neurological disorders (HAND). Until now, blood vessels were assumed to be the sole transport system by which HIV-infected monocytes entered the brain by bypassing a potentially hostile blood-brain-barrier through inflammatory-mediated semi-permeability. A cascade of specific chemokine signals promote monocyte migration from blood vessels to surrounding brain tissues via a well-supported endothelium, where the cells differentiate into tissue macrophages capable of productive HIV infection. Lymphatic vessels on the other hand are more loosely organized than blood vessels. They absorb interstitial fluid from bodily tissues where HIV may persist and exchange a variety of immune cells (CD4+ T-cells, monocytes, macrophages and dendritic cells) with surrounding tissues through discontinuous endothelial junctions. We propose that the newly discovered meningeal lymphatics are key to HIV migration among viral reservoirs and brain tissue during periods of undetectable plasma viral loads due to suppressive combinational antiretroviral therapy, thus redefining the migration process in terms of a blood-lymphatic transport system.

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer

“…Our finding of ongoing replication of HIV RNA and DNA in lymph node and spleen is consistent with these observations. The lymph system may serve as an alternative route for HIV-infected cells to migrate (31), which would explain our observation of the dispersal of viral population among tissues (i.e., no compartmentalization), as well the lack of detectable virus in the blood. Furthermore, a recent study suggested that the meninges may be part of the lymphatic system (32), which could provide an explanation of late infection in the brain noted previously (33) and shown in this study in the recent and rapid expansion in the cerebellum.…”

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

“…A recent study elegantly demonstrated that HIV reprograms macrophage migration, resulting in macrophage accumulation in patient tissues, a key step for virus spread and pathogenesis (89). Tumorassociated macrophages express vascular endothelial growth factors (36,71), and while viral loads in blood and CSF were negative for these participants, an interesting hypothesis is that the lymphatic system, which is more permeable than blood vessels for immune cell migration, may be an alternate migratory pathway for the dispersal of HIV virions or infected immune cells produced by tumors or plaque during cART (87,(90)(91)(92). All participants in the study had a degree of brain pathology (Table 6), and most had quantifiable brain HIV DNA at autopsy, suggesting that brain infection or even the damage caused by previous HIV assaults to the brain may significantly contribute to ongoing disease, even the non-brain-associated diseases noted in the cohort.…”

Strategies to target non-T-cell HIV reservoirs

“…Post-mortem brain tissue analysis has revealed that viral DNA is present in 3% to 19% of astrocytes 15 despite astrocyte infection being both relatively infrequent and unproductive 16 . Moreover, our group has used next generation in situ hybridization RNAScope to identify HIV vRNA in cerebellum macrophages of in an infected individual who died with no detectable viral load 17 . Therefore, it is of the utmost importance to consider the contribution of non CD4+ T cells as reservoirs and sources of HIV viremia.…”