Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia

Fractalkine (FKN), a chemokine highly expressed in the central nervous system, participates in inflammatory responses operative in many brain disorders including HIV-1 associated dementia (HAD). In this report, HIV-1 progeny virions and pro-inflammatory products led to FKN production associated with neuronal injury and apoptosis. FKN was produced by neurons and astrocytes; but differentially produced by the two cell types. Laboratory tests paralleled those in infected people where cerebrospinal fluid FKN levels in HIV-1 infected cognitively impaired (n=16) patients were found to be increased when compared to infected patients without cognitive impairment (n=8, P=0.0345). These results demonstrate a possible role of FKN in HAD pathogenesis.     

Neuroprotective strategies for HIV-1 associated dementia

The human immunodeficiency virus-1 (HIV-1) commonly affects cognitive, behavioral and motor functions during the disease course. The neuropathogenesis of viral infection revolves around neurotoxins produced from infected and immune-activated mononuclear phagocytes (MP; perivascular macrophages and microglia). Direct infection of neurons occurs rarely, if at all. Neurologic disease arises in part as a consequence of MP metabolic dysfunction. Although the advent of highly active antiretroviral therapy (HAART) has attenuated the incidence and severity of neurologic disease, it, nonetheless, remains a common and disabling problem for those living with HIV-1 infection. Adjunctive therapies are currently designed to ameliorate clinical outcomes and are included in the therapeutic armamentarium. Anti-inflammatory drugs that inhibit cytokines, chemokines and interferons linked to neurodegenerative processes can significantly ameliorate neuronal function. HIV-1 neurotoxins have the unique ability to up-regulate glycogen synthase kinase-3beta (GSK-3beta) activity that in turn elicits neuronal apoptosis. GSK-3beta inhibitors are neuroprotective in animal models of Neuro AIDS. They are also currently in Phase 1 clinical trials designed for safety and tolerability in patients with HIV-1 infection. Neurotrophins are only beginning to be realized for their therapeutic potential in HIV-1 associated neurologic disease. This review article provides a broad overview of neuroprotective strategies for HIV-1 infection and details how such strategies act and may be implemented for treatment of human disease.     

Rodent model systems for studies of HIV-1 associated dementia

Understanding of HIV-1 neuropathogenesis and development of rationale therapeutic approaches requires relevant animal models. The putative mechanisms of neuroinflammatory and neurotoxic events triggered by HIV-1 brain infection are reflected by a number of rodent models. These include transgenic animals (either expressing viral proteins or pro-inflammatory factors), infection with murine retroviruses, and severe combined immunodeficient (SCID) mice reconstituted with human lymphocytes and injected intracerebrally with HIV-1-infected human monocyte-derived macrophages. The potential importance and limitations of the models in reflecting human disease are discussed with emphasis on their utility for development of therapies to combat HIV-1-associated neurologic impairment.     

The signaling and apoptotic effects of TNF-related apoptosis-inducing ligand in HIV-1 associated dementia

HIV-1 Associated Dementia (HAD) develops during progressive HIV-1 infection and is characterized by cognitive impairments, behavioral disorders and potential progressive motor abnormality. Abnormal inflammation within the central nervous system (CNS), activation of macrophage/microglia and involvement of proinflammatory cytokines have been suggested as primary factors in the pathogenesis of HAD. Impairment of neuronal function and neuronal cell death are believed to be the end pathophysiological result of HAD. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, was suggested to participate in apoptotic cell death during HAD. As a death ligand, TRAIL was originally thought to target only tumor cells. TRAIL is not typically present in CNS; however, emerging data show that TRAIL can be induced by immune stimuli on macrophage and microglia, major disease effector cells during HAD. Upregulated TRAIL may then cause neuronal apoptosis through direct interaction with TRAIL receptors on neurons or through macrophage death-mediated release of neurotoxins. In this review, we summarize the pivotal role of TRAIL in HAD and TRAIL-initiated intracellular death cascades that culminate in neuronal apoptosis as observed in HAD.     

Neuropathological changes in early HIV-1 dementia

Early pathological abnormalities in human immunodeficiency virus (HIV-1)-related dementia have not been well documented. We report a homosexual man with fatigue and intermittent diarrhea in whom early HIV-1-related dementia was demonstrated during neurological screening in the Multicenter AIDS Cohort Study. Within 4 months he died of massive epistaxis, and the brain revealed astrocytosis of white matter and mild pallor of myelin staining in the absence of inflammation, multinucleated giant cells, and brain atrophy.     

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.     

Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia

In human immunodeficiency virus (HIV)-1-associated dementia (HAD), consequences of interactions between infiltrating monocytes and brain endothelial cells are not yet fully understood. This study investigated whether the blood-brain barrier is affected in brain tissue of patients suffering from HAD and whether it was possible to find a correlation with the presence or absence of monocytic cells, which have been suggested to play a major role in HAD. Immunohistochemical analysis for zonula occludens 1, a tight junction protein, and CD68, a macrophage marker, revealed that loss of tight junction immunoreactivity was highly correlated with monocyte infiltration and with HAD. This suggests that the presence of perivascular macrophages cells is associated with breakdown of the blood-brain barrier thereby facilitating infiltration of more monocytic cells hence enhancing disease progression.     

HIV-1 associated encephalopathy and myelopathy

HIV-1-associated en cephalopathy (HIVE) remains an important manifestation of advanced HIV infection despite recent advances in antiretroviral therapy. Special pharmacological and virological conditions predominate in the central nervous system (CNS). HIVE is characterized by "subcortical" dementia which becomes manifest as psychomotor slowing as well as mernory and concentration deficits. Deficits of central motor function are an invariable finding. Enhanced viral replication in immunocompetent CNS cells is believed to be the pathogenic basis of CNS disease. This process leads to neurotoxic effects elicited directly by viral products as well as indirectly by the immune response to the virus. HIV-1 associated myelopathy (HIVM) is the other CNS manifestion of advanced HIV-1 infection. The present consensus paper recommends diagnostic and therapeutic procedures in HIVE and HIVM and outlines the state of current research. Received: 16 February 2001 Accepted: 3 December 2001     

HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors

BackgroundNeuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties.MethodsTransgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection.ResultsTg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p < 0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p < 0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p < 0.05).ConclusionsHIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.     

Neuropsychological and neurological manifestations of HIV-1 dementia in drug users.

The cognitive and motor deficits associated with human immunodeficiency virus-1 (HIV-1) infection have been studied using neurological examination and neuropsychological tests. However, drug users with HIV-1 infection generally have been excluded from such studies. Forty-four well-characterized drug users stratified by Centers for Disease Control staging were administered a standardized neurological examination and a battery of neuropsychological tests under single-blind conditions designed to minimize the acute effects of psychoactive substances. The results of the blind neurological examination were consistent with the previously ascertained clinical staging of HIV-1 infection. The pattern of neuropsychological deficits across HIV-1 states was similar to those found in cohorts of homosexual men.     

Expression of monocyte markers in HIV-1 infected individuals with or without HIV associated dementia and normal controls in Bangkok Thailand

HIV Associated Dementia (HAD) is a complication of HIV infection in developed countries and is still poorly defined in resource-limited settings. In this study we investigated the expression of the monocyte phenotype CD14CD16HLADR and the inflammatory profiles in monocytes supernatants by surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry in a cohort of HAD and non-HAD Thai volunteers prior to the initiation of ARV. The CD14CD16HLADR phenotype was significantly increased in monocytes from HAD and non-HAD versus negative controls, but there was no difference in phenotype and in the secretion protein profiles between the two seropositive groups. In addition, monocytes supernatants from HAD and non-HAD did not induced apoptosis or cell death in brain aggregate culture. In conclusion it appears that HAD in Thai individuals has a different immunological profile then in North America cohorts.     

The regulation of alpha chemokines during HIV-1 infection and leukocyte activation: relevance for HIV-1-associated dementia

Cellular immunity against human immunodeficiency virus type 1 (HIV-1)-infected brain macrophages serves to prevent productive viral replication in the nervous system. Inevitably, during advanced disease, this antiretroviral response breaks down. This could occur through virus-induced dysregulation of lymphocyte trafficking. Thus, we studied the production of non-ELR-containing -chemokines and their receptor (CXCR3) expression in relevant virus target cells. Macrophages, lymphocytes, and astrocytes secreted -chemokines after HIV-1 infection and/or immune activation. Lymphocyte CXCR3-mediated chemotactic responses were operative. In all, -chemokine-mediated T cell migration continued after HIV-1 infection and the neuroinflammatory events operative during productive viral replication in brain.     

Depression and reversible dementia in an HIV-1 seropositive individual: Implications for the dementia syndrome of depression

Abstract

Neuropsychological test results for an human immunodeficiency virus (HIV-1) seropositive patient who experienced two episodes of depression with associated compromise of Cognitive function during each of the two periods of depression and following treatment for the depression are presented. The patient recovered between episodes and was tested after recovery from each episode. Results demonstrate that executive functions were disproportionately affected during depressive episodes.     

Neuropsychological abnormalities in patients with dementia in CRF 01_AE HIV-1 infection

HIV-associated dementia (HAD) is not firmly established in patients with circulating recombinant form (CRF) 01_AE HIV-1. In this study, we compared neuropsychological performance among 15 Thai individuals with HAD, 15 Thai individuals without HAD, and 30 HIV-negative control subjects. HIV-1 participants were highly active anti-retroviral therapy naive and matched by age, education, and CD4 count. Neuropsychological testing abnormalities were identified in most cognitive domains among HAD vs HIV-negative participants, confirming the presence of HAD in CRF01_AE.     

Experimental and potential future therapeutic approaches for HIV-1 associated dementia targeting receptors for chemokines, glutamate and erythropoietin

Severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia can occur after infection with the human immunodeficiency virus-1 (HIV-1). Infected peripheral immune-competent cells, in particular macrophages, infiltrate the central nervous system (CNS) and provoke a neuropathological response involving all cell types in the brain. HIV-1 infection results in activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways that result in disruption of neuronal and glial function. Despite many major improvements in the control of viral infection in the periphery, a truly effective therapy for HIV-1 associated dementia is currently not available. This review will discuss experimental and potentially future therapeutic strategies based on recently uncovered pathologic mechanisms contributing to neuronal damage induced by HIV-1.     

AIDS dementia complex and HIV-1 brain infection: Clinical-virological correlations

To evaluate the presence and distribution of central nervous system infection by human immunodeficiency virus type 1 (HIV-1), we used immunohistochemical methods to map the HIV-1 p24 core protein in the brains of 55 autopsied patients with acquired immunodeficiency syndrome (AIDS). In a subset of 40 of these patients who had undergone antemortem neurological evaluation of the AIDS dementia complex (ADC), we analyzed the relation between the severities of the viral infection and clinical dysfunction. Viral antigen was detected in macrophages and cells with morphological and immunohistochemical characteristics of microglia as well as multinucleated cells. The distribution of antigen-positive cells preferentially involved certain deep brain structures, especially the globus pallidus, other basal ganglia nuclei, and the central white matter. Overall, the presence and frequency of infected cells were highly correlated with the histological findings of multinucleated-cell encephalitis and in general with the clinical ADC stage. However, infection was often more limited than might be “anticipated” from the severity of patients' clinical dysfunction: Only 61% of patients with at least ADC stage 1 had detectable antigen and of these only approximately 30% of the brain sections were antigen positive. These results suggest a pathogenetic model of ADC where virus- or cell-coded toxins amplify the effect of limited brain infection.