Abstract
Despite the ability of combination antiretroviral treatment (cART) to reduce viral burden to nearly undetectable levels in cerebrospinal fluid and serum, HIV-1 associated neurocognitive disorders (HAND) continue to persist in as many as half the patients living with this disease. There is growing consensus that the actual substrate for HAND is destruction of normal synaptic architecture but the sequence of cellular events that leads to this outcome has never been resolved. To address whether central vs. peripheral myeloid lineage cells contribute to synaptic damage during acute neuroinflammation we injected a single dose of the HIV-1 transactivator of transcription protein (Tat) or control vehicle into hippocampus of wild-type or chimeric C57Bl/6 mice genetically marked to distinguish infiltrating and resident immune cells. Between 8–24 hr after injection of Tat, invading CD11b+ and/or myeloperoxidase-positive leukocytes with granulocyte characteristics were found to engulf both microglia and synaptic structures, and microglia reciprocally engulfed invading leukocytes. By 24 hr, microglial processes were also seen ensheathing dendrites, followed by inclusion of synaptic elements in microglia 7 d after Tat injection, with a durable microgliosis lasting at least 28 d. Thus, central nervous system (CNS) exposure to Tat induces early activation of peripheral myeloid lineage cells with phagocytosis of synaptic elements and reciprocal microglial engulfment of peripheral leukocytes, and enduring microgliosis. Our data suggest that a single exposure to a foreign antigen such as HIV-1 Tat can lead to long-lasting disruption of normal neuroimmune homeostasis with deleterious consequences for synaptic architecture, and further suggest a possible mechanism for enduring neuroinflammation in the absence of productive viral replication in the CNS.
Highlights
Despite the ability of combination antiretroviral treatment (cART) to efficaciously suppress replication of HIV-1, at least one-half of virus-infected persons develop HIV-1 associated neurocognitive disorders (HAND) [1,2]
Even though CD11b does not differentiate between leukocyte subtypes [31], we were able to distinguish between infiltrating leukocytes with a round morphology and brain-resident microglia with a ramified morphology, Examination of hippocampal tissue around the site of transcription protein (Tat) injection revealed that both Tat and saline caused microglial activation and fragmentation adjacent to the needle track at 8 hours following injection, with few infiltrating leukocytes (Figure 1, Panels A and E)
We stereotactically injected a single dose of HIV-1 Tat into murine hippocampus and cortex to study the temporal sequence of events that leads to the neuroinflammation and abnormal synaptic architecture associated with HAND
Summary
Despite the ability of cART to efficaciously suppress replication of HIV-1, at least one-half of virus-infected persons develop HIV-1 associated neurocognitive disorders (HAND) [1,2]. An early investigation of these neuropathologic events by Jones et al [9] demonstrated infiltration of neutrophils one day after intracerebroventricular administration of either single or repeated doses of Tat into rats, followed by macrophages and lymphocytes 6 d later They noted astrocytosis, apoptotic cells, ventriculomegaly and a decrease in hippocampal glutamate:GABA ratios, leading to the conclusion that inflammatory cell infiltration, glial activation and neurotoxicity could be triggered by the presence of Tat in the CNS. We do not yet know whether the microglial response to Tat-induced chemotaxis of peripheral inflammatory leukocytes in vivo is an attempt at host defense of normal synaptic architecture, but it is interesting to speculate that microglia may attack invading leukocytes, which enter the CNS in response to local neuroinflammation and chemokine release [48,54,55]. Our morphometric data (Figure S2, Panel D) demonstrate a 41% increase in leukocyte and microglial contact with neuronal structures, and when considered in the context of synaptic elements present as inclusions in microglia at 7 d (Figure 10, Panels E, F) and enduring microgliosis at 28 d (Figure 1, Panel D; Figure S1, Panels B, D), this seems like a reasonable supposition to be investigated in future studies
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