Development Of HIV-associated Dementia Research Articles

Aging sensitizes male mice to cognitive dysfunction induced by central HIV-1 gp120.

Although highly active antiretroviral therapy has led to improved prognosis and alleviation of some HIV-related disease complications, it has not provided complete protection against HIV-associated dementia. As the population of persons living with HIV grows older and aged persons represent a significant number of new infections, it is important to understand how HIV may affect the aged brain. In the current study, both adult and aged mice were treated with HIV gp120 and trained in a reference memory version of the water maze. Analysis of probe data revealed that aged animals treated with gp120 demonstrated profound decrements in water maze performance compared to gp120 treated young animals and saline treated aged or young animals. Additionally, we examined the neuroinflammatory responses in the aged and adult brain 4 h after treatment with gp120. Pro-inflammatory cytokines associated with neuroinflammation are known to be antagonistic to learning and memory processes and aged and adult animals treated with gp120 demonstrated similar increases in IL-1β and IL-6 in the hippocampus and cortex. Additionally, gp120 treatment was associated with an increase in MHCII gene expression, a marker of microglial activation, in the hippocampus. Although, the aged brain demonstrated a similar inflammatory profile at the time point measured, aged animals were more sensitive to cognitive dysfunction related to gp120 treatment. This finding supports the theory that aging may be a significant risk factor in the development of HIV-associated dementia.

Evidence for predilection of macrophage infiltration patterns in the deeper midline and mesial temporal structures of the brain uniquely in patients with HIV-associated dementia

BackgroundHIV-1 penetrates the central nervous system, which is vital for HIV-associated dementia (HAD). But the role of cellular infiltration and activation together with HIV in the development of HAD is poorly understood.MethodsTo study activation and infiltration patterns of macrophages, CD8+ T cells in relation to HIV in diverse CNS areas of patients with and without dementia. 46 brain regions from two rapidly progressing severely demented patients and 53 regions from 4 HIV+ non-dementia patients were analyzed. Macrophage and CD8+ T cell infiltration of the CNS in relation to HIV was assessed using immuno-histochemical analysis with anti-HIV (P24), anti-CD8 and anti-CD68, anti-S-100A8 and granzyme B antibodies (cellular activation). Statistical analysis was performed with SPSS 12.0 with Student's t test and ANOVA.ResultsOverall, the patterns of infiltration of macrophages and CD8+ T cells were indiscernible between patients with and without dementia, but the co-localization of macrophages and CD8+ T cells along with HIV P24 antigen in the deeper midline and mesial temporal structures of the brain segregated the two groups. This predilection of infected macrophages and CD8+ T cells to the middle part of the brain was unique to both HAD patients, along with unique nature of provirus gag gene sequences derived from macrophages in the midline and mesial temporal structures.ConclusionStrong predilection of infected macrophages and CD8+ T cells was typical of the deeper midline and mesial temporal structures uniquely in HAD patients, which has some influence on neurocognitive impairment during HIV infection.

HIV-1-Associated Dementia During HAART Therapy

Human immunodeficiency virus (HIV-1) is the responsible agent of acquired immunodeficiency syndrome (AIDS), a multi system disorder including the central nervous system (CNS). The CNS is an immunological privileged site providing a sanctuary and reservoir for HIV-1. Monocytes derived macrophages (MDM) and microglia play a critical role in the development of HIV-associated dementia (HAD). Although the use of highly active antiretroviral therapy (HAART) has led to a strong reduction of HAD incidence, the prevalence of minor HIV-1 associated cognitive impairment appears rising among AIDS patients. Various factors including toxicity, insurgence of drug resistance and sometimes limited access to HAART, contribute to this phenomenon. Independent evolution of drug resistance mutations in several areas of the CNS may emerge as consequence of incomplete suppression of HIV-1, probably related to poor penetration of antiretroviral drugs into CNS. The emergence of resistant virus in the CNS may considerable influence the outcome of neurological disease and also the reseeding of HIV-1 in the systemic circulation upon failure of therapy. In this review, we outline the current state of knowledge regarding the pathophysiology of CNS injury in HIV-1 infection and will focus on the effects of HAART on CNS.

Roles of MCP-1 in development of HIV-dementia

The encephalopathy caused by HIV, known clinically as HIV-associated dementia (HAD) and pathologically as HIV encephalitis (HIVE), results from intense infiltration of mononuclear cells, productive replication of the virus in monocyte-derived macrophages/microglia, abortive replication in astrocytes and activation of macrophages/microglia and astrocytes leading to neuronal degeneration in the brains of infected persons. Recent findings have suggested that development of HAD is based more on the activation process than on direct evidence of virus replication in the brain. Since HAD is based on the encephalitic process, major studies have been directed to the mechanisms regulating the inflammatory process. Monocyte chemoattractant protein 1, MCP-1, is a chemokine that is implicated in this process and also in the development of activation in the brain. In this review, we have attempted to identify mechanisms that induce expression of MCP-1 in the brain and the role that it plays in recruitment of mononuclear cells from blood to brain and in the activation processes of inflammatory and neural cells that lead to development of degenerative changes in the neuronal population.

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

HIV-1 gp120 Proteins Alter Tight Junction Protein Expression and Brain Endothelial Cell Permeability: Implications for the Pathogenesis of HIV-Associated Dementia

Breakdown of the blood-brain barrier (BBB) is commonly seen in patients with HIV-associated dementia (HAD) despite the lack of productive infection of the brain endothelium. It is likely that secreted viral products play a major role in BBB damage and the development of HAD. The objective of this study is to determine the effects of gp120 proteins on brain endothelial cell permeability and junctional protein expression. Our results showed that treatment of cultured human brain endothelial cells with gp120 for 24 hours results in increased permeability of the endothelial monolayer. Also, gp120 proteins caused disruption and downregulation of the tight junction proteins ZO-1, ZO-2, and occludin in these cells. Other junctional proteins such as claudin-1 and claudin-5 were unaffected by gp120 treatment. These data demonstrate that HIV gp120 proteins alter both the functional and molecular properties of the BBB, which could increase trafficking of HIV, infected cells, and toxic humoral factors into the central nervous system and contribute to the pathogenesis of HAD.

Cytotoxic Effects of Exposure to the Human Immunodeficiency Virus Type 1 Protein Tat in the Hippocampus Are Enhanced by Prior Ethanol Treatment

Long-term ethanol exposure leads to increases in the expression and/or sensitivity of NMDA-type glutamate receptors, effects that may contribute to the development of cytotoxicity in the brain. The human immunodeficiency virus 1 (HIV-1) transcription factor Tat is one of many viral proteins that may contribute to the development of HIV-associated dementia (HAD) by indirectly or directly promoting excess function of NMDA receptors. Thus, these studies examined the hypothesis that long-term ethanol pre-exposure would sensitize the hippocampus to Tat-induced cytotoxicity in an NMDA receptor-dependent manner. Organotypic slice cultures of rat hippocampus were exposed to a recombinant 86-amino acid form of Tat (Tat1-86) or a Tat deletion mutant devoid of amino acids 31 to 61 (TatDelta31-61; 0.1-100 nM) for 24 hr alone or during withdrawal from 10 days of ethanol exposure (50 mM in culture medium). Additional cultures were exposed to NMDA (5 microM) or the NMDA receptor channel blocker MK-801 (1 microM) during these treatments. Cellular injury in the CA1, CA3, and dentate gyrus regions of slice cultures was assessed by microscopy of propidium iodide fluorescence. Twenty-four hours of withdrawal from ethanol exposure did not produce overt cellular injury in any region of slice cultures. However, NMDA-induced toxicity was markedly increased in ethanol-pre-exposed cultures, an effect prevented by MK-801 (1 microM) coexposure. Treatment of cultures with Tat1-86 alone (> or = 0.1 nM) produced modest toxicity in each region of hippocampal cultures that was also blocked by MK-801 coexposure. In contrast, exposure to TatDelta31-61 did not alter propidium iodide fluorescence. Exposure of cultures to Tat1-86 (> or = 0.1 nM) during ethanol withdrawal resulted in a marked potentiation of Tat's toxic effects in each region of slice cultures, particularly the CA1 region. This potentiation of Tat neurotoxicity was significantly attenuated by coexposure of cultures to MK-801 (1 microM). These results indicate that long-term ethanol exposure sensitizes the hippocampus to the cytotoxic effects of Tat in an NMDA receptor-dependent manner. This may suggest that HIV-1-positive individuals who are alcohol dependent possess a heightened risk for the development of HAD. Furthermore, the NMDA receptor, particularly allosteric modulatory sites such as polyamine-sensitive sites, may be a therapeutic target to be investigated in the treatment of HAD.

Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10

HIV-1 Nef is expressed in astrocytes, but a contribution to neuropathogenesis and the development of HIV-associated dementia (HAD) remains uncertain. To determine the neuropathogenic actions of the HIV-1 Nef protein, the brain-derived (YU-2) and blood-derived (NL4-3) Nef proteins were expressed in neural cells using an alphavirus vector, which resulted in astrocyte death ( P < 0.001). Supernatants from Nef-expressing astrocytes also caused neuronal death, suggesting the release of neurotoxic molecules by astrocytes. Analysis of pro-inflammatory gene induction in astrocytes expressing Nef revealed increased IP-10 mRNA expression (4000-fold) that was Nef sequence dependent. Recombinant IP-10 caused selective cell death in neurons ( P < 0.001) but not astrocytes, and the cytotoxicity of supernatant from astrocytes expressing Nef YU-2 was blocked by an antibody directed against the chemokine receptor CXCR3 ( P < 0.001). SCID/NOD mice implanted with a Nef YU-2-expressing vector displayed abnormal motor behavior ( P < 0.05), neuroinflammation, and neuronal loss relative to controls. Analysis of mRNA levels in brains from patients with HAD also revealed increased expression of IP-10 ( P < 0.05), which was confirmed by immunoreactivity detected principally in astrocytes. Phylogenetic and protein structure analyses of Nef sequences derived from HIV/AIDS patients with and without HAD suggested viral evolution toward a neurotropic Nef protein. These results indicate that HIV-1 Nef contributes to neuropathogenesis by directly causing astrocyte death together with indirect neuronal death through the cytotoxic actions of IP-10 on neurons. Furthermore, Nef molecular diversity was evident in brain tissue among patients with neurological disease and which may influence IP-10 production by astrocytes.

HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors.

The release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV-associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV-1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain-derived Tat sequences from nondemented (Tat-ND) and demented (Tat-HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat-HAD protein exhibited elevated matrix metalloproteinase (MMP)-2 and -7 release and activation, but cells expressing Tat-ND did not exhibit enhanced MMP expression. Conditioned media from Tat-HAD-transfected cells caused significantly greater neuronal death (15.4 +/- 4.3%) than did Tat-ND (4.4 +/- 2.1%) or nontransfected (2.1 +/- 0.8%) cell-derived conditioned media. The neurotoxicity induced by Tat-HAD was inhibited by anti-MMP-2 or -7 antibodies (p < 0.005) but not by antibodies against MMP-9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat-HAD-transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs.