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. Author manuscript; available in PMC: 2017 Sep 1.

Published in final edited form as: J Neuroimmune Pharmacol. 2016 Jun 28;11(3):484–494. doi: 10.1007/s11481-016-9686-5

Combination of adjunctive and antiretroviral treatments for HAND. A vigorous innate immune response occurs as a direct consequence of brain mononuclear phagocytes (perivascular macrophages, microglia) infection that drives a pro-inflammatory and virotoxin-associated neurotoxic response. This is perpetuated by an autonomous amplification of cytokine activities like TNF-α and by a persistent chemotaxis of HIV-1 infected macrophages from periphery in the setting of a failure of immune responses or an absence of antiretroviral therapy. Meanwhile HIV-1 infected macrophages interrupt astroglial function and integrity by pro-inflammatory mediators, compromising the metabolic function and homeostasis of the CNS. Neuronal loss in HIV-1 encephalitis is associated with synaptic and dendritic damage. Overt synaptic loss is in turn linked to cognitive impairment induced by the brain's viral load (A). The chemokine gradient in diseased brain drives transduced macrophage constitutively expressing sTNFR:Fc to the inflammatory site. Local release of sTNFR:Fc reverses the pro-inflammatory microenvironment and blocks a cycle of autocrine and paracrine cytokines produced by sequestering the major pro-inflammatory mediator TNF-α (B). Delivery of nanoART using macrophage as carriage serves to control HIV-1 replication in the brain by bringing antiretroviral drugs to local sites of viral growth. The long-acting nanoformulated-antiretroviral medicines are in the same subcellular viral compartment within multivesicular bodies (MVBs). This serves to reduce viral loads and numbers of peripheral HIV-1 infected CD4+ T-cells. Drug levels are sustained in reservoirs of viral infection (C). Upon the suppression of persistent inflammation and clearance of viral brain reservoirs, the function and homeostasis of microglia, astrocyte and most neurons are maintained.

Combination of adjunctive and antiretroviral treatments for HAND. A vigorous innate immune response occurs as a direct consequence of brain mononuclear phagocytes (perivascular macrophages, microglia) infection that drives a pro-inflammatory and virotoxin-associated neurotoxic response. This is perpetuated by an autonomous amplification of cytokine activities like TNF-α and by a persistent chemotaxis of HIV-1 infected macrophages from periphery in the setting of a failure of immune responses or an absence of antiretroviral therapy. Meanwhile HIV-1 infected macrophages interrupt astroglial function and integrity by pro-inflammatory mediators, compromising the metabolic function and homeostasis of the CNS. Neuronal loss in HIV-1 encephalitis is associated with synaptic and dendritic damage. Overt synaptic loss is in turn linked to cognitive impairment induced by the brain's viral load (A). The chemokine gradient in diseased brain drives transduced macrophage constitutively expressing sTNFR:Fc to the inflammatory site. Local release of sTNFR:Fc reverses the pro-inflammatory microenvironment and blocks a cycle of autocrine and paracrine cytokines produced by sequestering the major pro-inflammatory mediator TNF-α (B). Delivery of nanoART using macrophage as carriage serves to control HIV-1 replication in the brain by bringing antiretroviral drugs to local sites of viral growth. The long-acting nanoformulated-antiretroviral medicines are in the same subcellular viral compartment within multivesicular bodies (MVBs). This serves to reduce viral loads and numbers of peripheral HIV-1 infected CD4+ T-cells. Drug levels are sustained in reservoirs of viral infection (C). Upon the suppression of persistent inflammation and clearance of viral brain reservoirs, the function and homeostasis of microglia, astrocyte and most neurons are maintained.