Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS (original) (raw)
Related papers
Breaking down the barrier: The effects of HIV-1 on the blood–brain barrier
Brain Research, 2011
Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4+ T cells and cells of the monocyte-macrophage lineage, resulting in immunodeficiency in an infected patient. Along with this immune deficiency, HIV-1 has been linked to a number of neurological symptoms in the absence of opportunistic infections or other co-morbidities, suggesting that HIV-1 is able to cross the blood-brain barrier (BBB), enter the central nervous system (CNS), and cause neurocognitive impairment. HIV-1-infected monocyte-macrophages traverse the BBB and enter the CNS throughout the course of HIV-1 disease. Once in the brain, both free virus and virus-infected cells are able to infect neighboring resident microglia and astrocytes and possibly other cell types. HIV-1-infected cells in both the periphery and the CNS give rise to elevated levels of viral proteins, including gp120, Tat, and Nef, and of host inflammatory mediators such as cytokines and chemokines. It has been shown that the viral proteins may act alone or in concert with host cytokines and chemokines, affecting the integrity of the BBB. The pathological end point of these interactions may facilitate a positive feedback loop resulting in increased penetration of HIV into the CNS. It is proposed in this review that the dysregulation of the BBB during and after neuroinvasion is a critical component of the neuropathogenic process and that dysregulation of this protective barrier is caused by a combination of viral and host factors including secreted viral proteins, components of the inflammatory process, the aging process, therapeutics, and drug or alcohol abuse.
Chemokine receptor mRNA expression at the in vitro blood-brain barrier during HIV infection
NeuroReport, 1999
VIRAL entry through the blood±brain barrier (BBB) has not been fully de®ned and identi®cation of coreceptors that can facilitate this phenomenon is crucial in understanding disease progression. Using a RNAse protection assay to examine chemokine receptor families simultaneously, we analyzed the total RNA of in vitro BBB cultures treated with puri®ed preparations of HIV gp120, gp41, TAT proteins and TNF-á. HIV tat protein affected CCR1 and CCR3 mRNA expression whereas the other viral by-products had no effect. Interestingly, TNF-á was able to induce CCR1, CCR3 as well as CXCR1, CXCR2, CXCR4 receptors and Burkitt's lymphoma receptor BLR2. These results suggest that HIV-induced molecules can manipulate the surface receptor expression of the BBB to allow for their preferential entry into brain. NeuroReport 10:53± 56 # 1999 Lippincott Williams & Wilkins.
Microglial Cells: The Main HIV-1 Reservoir in the Brain
Frontiers in Cellular and Infection Microbiology, 2019
Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.
AIDS and the blood-brain barrier
Journal of NeuroVirology
The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency virus (SIV) in macaques. In this review, we provide an overview of the function, structure, and components of the BBB, followed by a more detailed discussion of the subcellular structures and regulation of the tight junction. We then discuss the ways in which HIV/SIV affects the BBB, largely through infection of monocytes/macrophages, and how infected macrophages crossing the BBB ultimately results in breakdown of the barrier. Journal of NeuroVirology (2009) 15, 111Á122.
Journal of Neuroimmune Pharmacology, 2016
Blood brain barrier (BBB) damage is a common feature in central nervous system infections by HIV and it may persist despite effective antiretroviral therapy. Astrocyte involvement has not been studied in this setting. Patients were enrolled in an ongoing prospective study and subjects with central nervous system-affecting disorders were excluded. Patients were divided into two groups: treated subjects with cerebrospinal fluid (CSF) HIV RNA <50 copies/mL (CSFcontrollers) and in late-presenters CD4+ T lymphocytes <100/uL. CSF biomarkers of neuronal or astrocyte damage were measured and compared to CSF serum-to-albumin ratio. 134 patients were included; 67 subjects in each group (50 %) with similar demographic characteristics (with the exception of older age in CSF controllers). CD4 (cells/uL), plasma and CSF HIV RNA (Log 10 copies/mL) were 43 (20-96), 5.6 (5.2-6) and 3.9 (3.2-4.7) in LPs and 439 (245-615), <1.69 (9 patients <2.6) and <1.69 in CSFc. BBB impairment was observed in 17 late-presenters (25.4 %) and in 9 CSFcontrollers (13.4 %). CSF biomarkers were similar but for higher CSF neopterin values in late-presenters (2.3 vs. 0.6 ng/mL, p < 0.001). CSARs were associated with CSF neopterin (rho = 0.31, p = 0.03) and HIV RNA (rho = 0.24, p = 0.05) in late-presenters and with CSF tau (rho = 0.51, p < 0.001), p-tau (rho = 0.47, p < 0.001) and S100beta (rho = 0.33, p = 0.009) in CSF-controllers. In HAART-treated subjects with suppressed CSF HIV RNA, BBB altered permeability was associated with markers of neuronal damage and astrocytosis. Additional treatment targeting astrocytosis and/ or viral protein production might be needed in order to reduce HIV effects in the central nervous system.
The neuropathogenesis of HIV1 infection
Fems Immunology and Medical Microbiology, 1999
HIV encephalitis is the common pathologic correlate of HIV-dementia (HAD). HIV-infected brain mononuclear phagocytes (MP) (macrophages and microglia) are reservoirs for persistent viral infection. When activated, MP contribute to neuronal damage. Such activated and virus-infected macrophages secrete cellular and viral factors, triggering neural destructive immune responses. Our Center's laboratories have begun to decipher the molecular and biochemical pathways for MP-mediated neuronal damage in HAD. This review will discuss the salient clinical and pathological features of HAD and highlight the recent advances made, by our scientists and elsewhere, in unraveling disease mechanisms, including the role of chemokines and their receptors in the neuropathogenesis of HIV-1 encephalitis. ß