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A human immunodeficiency virus type 1 (HIV) -seropositive, antiretroviral-naive patient presented with significant cognitive dysfunction. Neuropsychologic, neuroradiologic, immunologic, and virologic studies confirmed HIV-associated dementia (HAD). After 12 weeks of highly active antiretroviral therapy (HAART) with ibuprofen, dramatic improvements were demonstrated in neurologic function and were sustained for ú1 year. HIV-1 RNA in cerebrospinal fluid (CSF) decreased from 10 5 to 10 4 copies/mL after 4 weeks. After 20 weeks of therapy, plasma viremia decreased from 10 6 copies/mL to undetectable (õ96 copies/mL). Assays of neurotoxins (tumor necrosis factor-a, quinolinic acid, and nitric oxide) in plasma and CSF were considerably elevated at presentation and significantly decreased after therapy. Baseline plasma and CSF demonstrated neurotoxic activities in vitro, which also reduced markedly. These data, taken together, support the notion that HAD is a reversible metabolic encephalopathy fueled by viral replication. HAART used with nonsteroidal antiinflammatory agents leads to the suppression of inflammatory neurotoxins and can markedly improve neurologic function in HAD.Human immunodeficiency virus type 1 (HIV)-associated deproteins such as gp120, tat, and nef [18][19][20][21][22]. High levels of these macrophage-produced neurotoxic factors have been found mentia (HAD) is characterized by cognitive and motor impairment in 15%-20% of infected patients [1][2][3][4]. Neurologic defiin the brains and cerebrospinal fluid (CSF) of patients with HAD [23][24][25][26]. These factors produce an encephalopathy with cortical cits have been classified by the American Academy of Neurology, and an algorithm has been developed for mild disand subcortical neuronal damage [27] and induce a breakdown of the blood-brain barrier (BBB) [28, 29]. ease (minor cognitive/motor disorder) or more severe impairment (HAD) [1]. Dementia can occur with few neuropathologic HIV RNA levels in CSF correlate with the presence and severity of cognitive dysfunction [30 -33]. If a central nervous changes or with encephalitis characterized by multinucleated giant cells, astrocytosis, microglial nodules, myelin pallor, and system virus is both necessary and sufficient to induce neurologic impairment, therapy for HAD should of necessity target neuronal loss [5,6]. Of interest, clinical disease is not caused by active HIV replication in neural cells. The virus's target cells HIV. Inhibitors of HIV protease in combination with nucleoside analogue reverse transcriptase (RT) inhibitors can dramatiare mononuclear phagocytes (brain macrophages and microglia) [7,8]. Once infected, these cells become immunoactive and cally reduce levels of plasma viremia [34,35]. Unfortunately, many of these agents are highly plasma protein bound and have produce a variety of neurotoxic secretory products [9]. These include but are not limited to cytokines such as tumor necrosis limited BBB penetration [36]. Zidovudine remains the only drug to date with documented efficacy for H...

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Human immunodeficiency virus type 1 (HIV-1) infection in mononuclear phagocyte lineage cells (monocytes, macrophages, and microglia) is a critical component in the pathogenesis of viral infection. Viral replication in macrophages serves as a reservoir, a site of dissemination, and an instigator for neurological sequelae during HIV-1 disease. Recent studies demonstrated that chemokine receptors are necessary coreceptors for HIV-1 entry which determine viral tropism for different cell types. To investigate the relative contribution of the β-chemokine receptors CCR3 and CCR5 to viral infection of mononuclear phagocytes we utilized a panel of macrophage-tropic HIV-1 strains (from blood and brain tissue) to infect highly purified populations of monocytes and microglia. Antibodies to CD4 (OKT4A) abrogated HIV-1 infection. The β chemokines and antibodies to CCR3 failed to affect viral infection of both macrophage cell types. Antibodies to CCR5 (3A9) prevented monocyte infection but only slowed HIV replication in microglia. Thus, CCR5, not CCR3, is an essential receptor for HIV-1 infection of monocytes. Microglia express both CCR5 and CCR3, but antibodies to them fail to inhibit viral entry, suggesting the presence of other chemokine receptors for infection of these cells. These studies demonstrate the importance of mononuclear phagocyte heterogeneity in establishing HIV-1 infection and persistence.

Productive replication of human immunodeficiency virus type 1 (HIV-1) in brain macrophages and microglia is a critical component of viral neuropathogenesis. However, how virus-macrophage interactions lead to neurological disease remains incompletely understood. Possibly, a differential ability of virus to replicate in brain tissue macrophages versus macrophages in other tissues underlies HIV-1 neurovirulence. To these ends, we established systems for the isolation and propagation of pure populations of human microglia and then analyzed the viral life cycles of divergent HIV-1 strains in these cells and in cultured monocytes by using identical viral inocula and indicator systems. The HIV-1 isolates included those isolated from blood, lung tissue, cerebrospinal fluids (CSF), and brain tissues of infected subjects: HIV-1ADA and HIV-189.6 (from peripheral blood mononuclear cells), HIV-1DJV and HIV-1JR-FL (from brain tissue), HIV-1SF162(from CSF), and HIV-1BAL (from lung tissue). The synthesis of viral nucleic acids and viral mRNA, cytopathicity, and release of progeny virions were assessed. A significant heterogeneity among macrophage-tropic isolates for infection of monocytes and microglia was demonstrated. Importantly, a complete analysis of the viral life cycle revealed no preferential differences in the abilities of the HIV-1 strains tested to replicate in microglia and/or monocytes. Macrophage tropism likely dictates the abilities of HIV-1 to invade, replicate, and incite disease within its microglial target cells.