Upregulation of microglia in drug users with and without pre‐symptomatic HIV infection

Abstract

It is generally thought that infection of the central nervous system (CNS) by HIV-1 can occur early, even around the time of seroconversion, and evidence from animal studies supports this. However, the mode and timing of viral entry remain poorly understood since there have been comparatively few studies of the early neuropathology of HIV infection. In this study, samples of frontal and temporal lobes, and basal ganglia, were selected from 12 HIV-positive drug users who had been infected for 4-130 months before death, 10 HIV-negative drug users and 10 non-drug using controls, all age and sex matched. Routine and immunocytochemical staining showed that leptomeningeal and perivascular lymphocytic infiltrate was upregulated in HIV-infected cases compared with the two control groups, and choroid plexitis was confined to the HIV-positive subjects, suggesting an association with viral infection. In contrast, CD68-positive microglia were enhanced in both HIV- positive and HIV-negative drug users, considerably above the baseline seen in normal controls. However, there was no statistical difference between the three groups in relation to astrocytes. Screening and competitive polymerase chain reaction (PCR) undertaken on multiple samples including brain tissue, choroid plexus and leptomeninges from four of the HIV-positive subjects and one control case showed that the pro-viral burden was never more than 13 copies/microg DNA and was negative in multiple samples from one HIV-positive case and one control case. All the basal ganglia samples were PCR-negative. This study has not revealed any t spots' of viral load in brain tissue, choroid plexus or meninges, either early or late in the course of pre-symptomatic HIV infection. Drug use alone is associated with significant upregulation of microglia and this may predispose to HIV infection of the nervous system in drug users.

CD163, a Marker of Perivascular Macrophages, Is Up-Regulated by Microglia in Simian Immunodeficiency Virus Encephalitis after Haptoglobin-Hemoglobin Complex Stimulation and Is Suggestive of Breakdown of the Blood-Brain Barrier

“…Infection of these cells is thought to be critical in the pathogenesis of neuroAIDS and the development of HIV and SIV encephalitis (HIVE/SIVE). [1][2][3][4][5][6][7][8][9][10] Although there is consensus that macrophages in the CNS are infected, these cells are heterogeneous with respect to their morphology, location, and function. At least four distinct populations of CNS macrophages exist.…”

κ-Opioid Receptor Ligands Inhibit Cocaine-Induced HIV-1 Expression in Microglial Cells

“…Based upon a substantial literature demonstrating that substances of abuse, such as cocaine and opiates, can both impair the function of CD4 ϩ lymphocytes and macrophages (Klein et al, 1993, Mao et al, 1996, Baldwin et al, 1997, Eisenstein and Hilburger, 1998Friedman et al, 2003) and potentiate the expression of HIV-1 in these cells (Peterson et al, 1990(Peterson et al, , 1992Bagasra and Pomerantz, 1993;Nair et al, 2000, Li et al, 2002Roth et al, 2002;Steele et al, 2003), it has been postulated that abuse of these drugs may serve as a cofactor in the progression of HIV-1 infection. The role of substances of abuse in development of HIV-1-associated dementia (HAD), one of the most devastating complications of AIDS, is supported by a growing body of epidemiological and histopathological evidence (Wang et al, 1995;Davies et al, 1997;Bell et al, 1998;Bouwan et al, 1998;Goodkin et al, 1998;Tomlinson et al, 1999), as well as by studies of molecular mechanisms whereby drugs of abuse and HIV-1 interact in causing neuronal death (Nath et al, 2002).…”

The Changing Pathology of NeuroAIDS Associated with Drug Abuse in the Era of HAART

“…Dopaminergic neurons may be at risk when exposed to amphetamines and opiates [83] . Subtle neuronal damage and/or intermittent hypoxic damage may be the cause of microglial activation which is also observed in the brains of regular drug abusers [41,84] . These activated cells are able to release cytokines, particularly tumour necrosis factor alpha, which are pro-inflammatory and potentially neurotoxic [85] .…”

“…Since these individuals have died of causes unrelated to HIV and apparently before the onset of AIDS, it is unlikely that AIDS related HIV encephalitis or CNS opportunistic conditions are present. Other subtle cellular reactions occur in the brain in pre-AIDS including microglial activation and astrocytosis [13,41] . HIV can be detected by PCR at low level within brain tissue in pre-AIDS [40,42] .…”