The pathogenesis of human immunodeficiency virus (HIV)-associated dementia is unclear, and the underlying pathological substrate has been a matter of debate. In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV-associated dementia and the presence and relative quantity of immunocytochemical markers for HIV-1 (gp41 antibody), and for macrophages and microglia (HAM-56 antibody). Sections from the basal ganglia and frontal lobes from the brains of 51 patients were studied, and the data were stratified for severity of dementia (16 nondemented, 12 mildly demented, 23 severely demented), rate of dementia progression, duration of AIDS, use of antiretrovirals, and several other demographic features. We found a highly significant correlation between the degree of macrophage staining and the severity of dementia but only a borderline correlation between the presence and amount of gp41-positive cells and dementia. Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity. Other correlations with the immunostaining data, including antiretroviral use, were not significant. We conclude that the presence of macrophages and microglia is a better correlate with HIV-associated dementia than is the presence and amount of HIV-infected cells in the brain. These data support the concept that the pathogenesis of HIV-associated dementia is likely due to indirect effects of HIV infection of the brain, possibly through the actions of macrophages and microglia.
"The chronic nature of HIV-1 replication in cells of the monocyte-macrophage lineage is likely a contributor to the central importance of these cells in evasion of HIV-1 detection and elimination by the immune system and the maintenance of viral reservoirs. The virus can utilize cells of this lineage as a vehicle facilitating its transport across the blood–brain barrier (BBB) and its entry into the CNS [14-16], thereby promoting HIV-1-associated neuropathogenesis and the development of minor neurocognitive impairment, as well as the more severe CNS disease, HIV-1-associated dementia (HIVD). HIV-1 infection of the CNS occurs soon after infection; however, under most circumstances, prolonged productive viral replication, characterized by the formation of multinucleated giant cells with progressive loss of cognitive, behavioral, and motor deficits, is likely to occur only after severe immunosuppression and breakdown of the BBB. "
[Show abstract][Hide abstract] ABSTRACT: Background
HIV-1 gene expression is driven by the long terminal repeat (LTR), which contains many binding sites shown to interact with an array of host and viral factors. Selective pressures within the host as well as the low fidelity of reverse transcriptase lead to changes in the relative prevalence of genetic variants within the HIV-1 genome, including the LTR, resulting in viral quasispecies that can be differentially regulated and can potentially establish niches within specific cell types and tissues.
Utilizing flow cytometry and electromobility shift assays, specific single-nucleotide sequence polymorphisms (SNPs) were shown to alter both the phenotype of LTR-driven transcription and reactivation. Additional studies also demonstrated differential loading of transcription factors to probes derived from the double-variant LTR as compared to probes from the wild type.
This study has identified specific SNPs within CCAAT/enhancer binding protein (C/EBP) site I and Sp site III (3 T, C-to-T change at position 3, and 5 T, C-to-T change at position 5 of the binding site, respectively) that alter LTR-driven gene transcription and may alter the course of viral latency and reactivation. The HIV-1 LAI LTRs containing the SNPs of interest were coupled to a plasmid encoding green fluorescent protein (GFP), and polyclonal HIV-1 LTR-GFP stable cell lines utilizing bone marrow progenitor, T, and monocytic cell lines were constructed and utilized to explore the LTR phenotype associated with these genotypic changes.
Although the 3 T and 5 T SNPs have been shown to be low-affinity binding sites, the fact that they can still result in effective HIV-1 LTR-driven gene expression, particularly within the TF-1 cell line, has suggested that the low binding site affinities associated with the 3 T C/EBP site I and 5 T Sp site III are potentially compensated for by the interaction of nuclear factor-κB with its corresponding binding sites under selected physiological and cellular conditions. Additionally, tumor necrosis factor-α and Tat can enhance basal transcription of each SNP-specific HIV-1 LTR; however, differential regulation of the LTR is both SNP- and cell type-specific.
"It has been proposed that HIV-1 can invade the CNS via virusinfected monocytes and CD4 þ T cells that cross the BBB (Fischer- Smith et al., 2001; Glass et al., 1995; Haas et al., 2000, 2003; Harrington et al., 2005; Persidsky et al., 1999; Schnell et al., 2011; Wang et al., 2008). Until now, most studies have focused on the neuroinvasion of HIV-1 via monocytes. "
[Show abstract][Hide abstract] ABSTRACT: Eicosanoids, including cysteinylleukotrienes (cysLTs), are found in the central nervous system (CNS) of individuals infected with HIV-1. Few studies have addressed the contribution of cysLTs in HIV-1-associated CNS disorders. We demonstrate that conditioned medium from human astrocytes treated with leukotriene C4 (LTC4) increases the transmigration of HIV-1-infected CD4+ T cells across an in vitro blood–brain barrier (BBB) model using cultured brain endothelial cells. Additional studies indicate that the higher cell migration is linked with secretion by astrocytes of CX3CL1/fractalkine, a chemokine that has chemoattractant activity for CD4+ T cells. Moreover, we report that the enhanced cell migration across BBB leads to a more important CD4+ T cell-mediated HIV-1 transfer toward macrophages. Altogether data presented in the present study reveal the important role that LTC4, a metabolite of arachidonic acid, may play in the HIV-1-induced neuroinvasion, neuropathogenesis and disease progression.
Virology 04/2014; s 454–455(1):128–138. DOI:10.1016/j.virol.2014.02.007 · 3.32 Impact Factor
"Neuroinflammation is a common feature observed throughout the progression of the disease from the latent, asymptomatic stage of AIDS to HAD . Circulating monocytes and macrophages have the ability to traverse the intact BBB and undergo differentiation within brain parenchyma, giving rise to long-lived brain resident macrophages and microglia . "
[Show abstract][Hide abstract] ABSTRACT: HIV-1 associated dementia remains a significant public health burden. Clinical and experimental research has shown that reduced levels of brain-derived neurotrophic factor (BDNF) may be a risk factor for neurological complications associated with HIV-1 infection. We are actively testing genetically modified macrophages for their possible use as the cell-based gene delivery vehicle for the central nervous system (CNS). It can be an advantage to use the natural homing/migratory properties of monocyte-derived macrophages to deliver potentially neuroprotective BDNF into the CNS, as a non-invasive manner. Lentiviral-mediated gene transfer of human (h)BDNF plasmid was constructed and characterized. Defective lentiviral stocks were generated by transient transfection of 293T cells with lentiviral transfer plasmid together with packaging and envelope plasmids. High titer lentiviral vector stocks were harvested and used to transduce human neuronal cell lines, primary cultures of human peripheral mononocyte-derived macrophages (hMDM) and murine myeloid monocyte-derived macrophages (mMDM). These transduced cells were tested for hBDNF expression, stability, and neuroprotective activity. The GenomeLab GeXP Genetic Analysis System was used to evaluate transduced cells for any adverse effects by assessing gene profiles of 24 reference genes. High titer vectors were prepared for efficient transduction of neuronal cell lines, hMDM, and mMDM. Stable secretion of high levels of hBDNF was detected in supernatants of transduced cells using western blot and ELISA. The conditioned media containing hBDNF were shown to be protective to neuronal and monocytic cell lines from TNF-α and HIV-1 Tat mediated cytotoxicity. Lentiviral vector-mediated gene transduction of hMDM and mMDM resulted in high-level, stable expression of the neuroprotective factorBDNF in vitro. These findings form the basis for future research on the potential use of BDNF as a novel therapy for neuroAIDS.
PLoS ONE 02/2014; 9(2):e82030. DOI:10.1371/journal.pone.0082030 · 3.23 Impact Factor
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