Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients

Bell, Jeanne E.; Donaldson, Y K; Lowrie, Suzanne; McKenzie, Chris Anne; Elton, R. A.; Chiswick, Ann; Brettle, R.P.; Ironside, James; Simmonds, Peter

doi:10.1097/00002030-199605000-00007

Cited by 87 publications

(68 citation statements)

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“…Our ®ndings may be relevant for other viral infections of the brain, like HIV, in which activation of the glia cells, e.g. by dopamimetic substances, could rather be harmful than helpful (Bell et al, 1996;Davies et al, 1997;Martinez et al, 1995).…”

Section: Discussionmentioning

confidence: 85%

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Czub¹,

Czub²,

Gosztonyi³

et al. 1999

J Neurovirol

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Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-in¯ammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which ± under different conditions ± exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) signi®cantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

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Section: Discussionmentioning

confidence: 85%

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Czub¹,

Czub²,

Gosztonyi³

et al. 1999

J Neurovirol

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“…HIV infection in the majority of Edinburgh IDUs, including those described in the present study, originated from a common source introduced into a specific suburb of Edinburgh around 1982-1983 (12, 40, 64). Despite careful analysis of compounding factors, such as treatment compliance and risk-taking behavior, it has remained difficult to account for the much higher incidence of GCE in this group than in other risk groups in Edinburgh or in IDU cohorts in other cities (8,9). One possibility is that the virus introduced into this group has a greater propensity for infection of macrophages than other subtype B variants of HIV.…”

Section: Fig 6 (A)mentioning

confidence: 99%

Identification of Shared Populations of Human Immunodeficiency Virus Type 1 Infecting Microglia and Tissue Macrophages outside the Central Nervous System

Wang

Donaldson

Brettle³

et al. 2001

J Virol

184

180

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Infection of microglia and other cells of the macrophage/monocyte lineage in the central nervous system (CNS) by human immunodeficiency virus type I (HIV-1) underlies the development of giant cell encephalitis (GCE). It is currently unknown whether GCE depends on the emergence of virus populations specifically adapted to replicate in cells of the monocyte/macrophage lineage and whether this also leads to the specific targeting of macrophages in other nonlymphoid tissues. Autopsy samples from lymph node, brain (frontal region), lung, and full-thickness colon sections were obtained from nine study subjects with GCE and from nine without. The two groups showed no significant differences in CD4 counts, disease progression, or treatment history before death. Genetic relatedness between variants recovered from lymph node and nonlymphoid tissues was assessed by sequence comparison of V3 and p17 gag regions using a newly developed method that scores the sample composition at successive nodes in a neighbor-joining tree. The association index enabled objective, numerical comparisons on the degree of tissue compartmentalization to be made. High proviral loads and p24 antigen expression in the brain were confined to the nine individuals with GCE. GCE was also associated with significantly higher proviral loads in colon samples (median of the GCE ؉ group: 1,010 copies/10 6 cells; median of GCE ؊ group, 10/10 6 cells; P ‫؍‬ 0.006). In contrast, there were no significant differences in proviral load between the GCE ؉ and GCE ؊ groups in lymph node or lung samples, where HIV infection was manifested predominantly by infiltrates of lymphoid cells. V3 sequences from brain samples of individuals with GCE showed the greatest compartmentalization from those of lymph node, although samples from other tissues, particularly the colon, frequently contained variants phylogenetically related to those found in brain. The existence of shared, distinct populations of HIV specifically distributed in cells of the monocyte/ macrophage lineage was further indicated by immunocytochemical detection of CD68 ؉ , multinucleated giant cells expressing p24 antigen in samples of lung and colon in two individuals with GCE. This study provides the basis for future investigation of possible phenotypic similarities that underline the shared distributions of HIV variants infecting microglia and tissue macrophages outside the CNS.

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“…We and others have reported that, prior to the advent of HAART, HIVE occurred more frequently in drug users with AIDS than in other risk groups [89,90] but this has not been universal experience [35,91,92] . For drug users enrolled in HAART regimes, the major cause of death is now hepatitis, which may be difficult to treat in the context of HIV co-infection.…”

Section: The Stages Of Neuroaids Pathology Prior To 1996mentioning

confidence: 94%

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

Bell¹,

Anthony²,

Simmonds³

2006

American J. of Infectious Diseases

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Compliance with highly active antiretroviral therapy (HAART) arrests HIV induced immune collapse and reduces the prevalence of severe central nervous system (CNS) complications, including HIV associated dementia and encephalitis. However minor cognitive disorders remain common and recent autopsy studies have demonstrated the presence of subtle neuropathological abnormalities in HAART treated individuals, including persistent neuroinflammation and enhanced deposition in the brain of proteins associated with neurodegeneration. The closest comparison group from the pre-HAART era is that comprising presymptomatic HIV infected individuals dying from non HIV related causes. HIV is believed to enter the CNS at or soon after the time of initial infection. Whether this occurs in all HIV infected individuals is unknown. The virus is probably restrained from progressing to a productive CNS infection by systemic and innate immune controls which include surveillance of brain tissue by patrolling CD8 lymphocytes. However HIV is not eliminated from the CNS compartment and is present at low level in the brains of some HAART treated just as in pre-HAART subjects. Brain viral isolates appear to be neuroadapted and clearly persist long term in the sanctuary of the CNS. This review compares and contrasts data derived from studies of the brain in pre and post HAART cohorts. The implications of increasing longevity in treated individuals who may have low level HIV infection of brain tissue, associated with lymphocytic infiltration and microglial/macrophage activation, are discussed. The exact roles of these cellular reactions in relation to viral suppression are unclear at present. The complexity of this scenario is further heightened when other factors such as illicit drug intake and hepatitis-induced encephalopathy contribute to the clinical outcome. These added insults lead to damaging effects in the brain which may augment those induced by HIV/AIDS. Taken together, these factors suggest that the incidence of HIV-related CNS disorders will rise again in the future.

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Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients

Cited by 87 publications

References 0 publications

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Effects of Selegiline in a retroviral rat model for neurodegenerative disease

Identification of Shared Populations of Human Immunodeficiency Virus Type 1 Infecting Microglia and Tissue Macrophages outside the Central Nervous System

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

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