Unique monocyte subset in patients with AIDS dementia

doi:10.1016/S0140-6736(96)10178-1

The Lancet

Volume 349, Issue 9053, 8 March 1997, Pages 692-695

https://doi.org/10.1016/S0140-6736(96)10178-1 Get rights and content

Summary

Background

15–30% of patients infected with HIV will develop a debilitating dementia. Whilst HIV enters the brain soon after infection, presumably within monocyte-derived macrophages, not all patients with HIV become demented. Blood monocytes probably cross the blood-brain barrier and give rise ultimately to parenchyma macrophages. We looked for a specific monocyte subset in AIDS patients with dementia.

Methods

Peripheral blood monocytes from three groups were compared: AIDS patients with (n= 12) and without (n= 11) dementia, and ten HIV seronegative healthy controls. We used flow cytometry to analyse monocytes, and cell lysis and apoptosis assays to examine monocyte effects on human brain cells in vitro.

Findings

We found a unique subset of monocytes in patients with AIDS dementia. These monocytes were more dense and granular and expressed CD14/CD16 and CD14/CD69. Means (SD) for CD14/CD16 in HIV-negative controls and in AIDS non-dementia and AIDS dementia patients were 6·5% (4), 16% (13), and 37% (21), respectively (p=0·008 between the two groups of patients). The corresponding means for CD14/CD69 were 7% (6), 8% (10), and 69% (18) (p<0·0001).

Interpretation

CD69 is a member of the natural-killer-cell gene complex that is expressed after activation. Supernatants from cultures containing these dense cells can trigger apoptosis of human brain cells in vitro. The monocyte subset we found in patients with AIDS dementia might enter the brain and expose neural cells to toxic factors.

Introduction

Although the CD4 T-cell is the main peripheral-blood target of HIV, the macrophage is the cell predominantly infected in the brain. The monocyte, unlike the CD4 lymphocyte, is infected in a chronic non-lytic manner. The HIV-infected monocyte-derived macrophage may enter into the brain early in infection;¹ however, dementia occurs late in most patients, especially in severe immunosuppression. Investigators disagree about the mechanism(s) responsible for the cognitive dysfunction associated with AIDS, although most believe it is an indirect mechanism associated with macrophages.2, 3, 4 There is a stronger correlation between the presence and number of macrophages in the brain in AIDS dementia than the number of cells positive for HIV-1 antigen.² Soluble factors produced from HIV-infected monocyte-derived macrophages are neurotoxic in vitro.3, 4 Specific factors produced from chronically activated and/or HIV-infected macrophages include tissue necrosis factor α (TNFα),5, 6 platelet-activating factor,7, 8 arachidonic acid metabolites,7, 9 and quinolinic acid.10, 11 Only TNFα and quinolinic acid are increased in the brains of patients with AIDS dementia.¹² We have examined peripheral-blood mononuclear cells from HIV-infected patients to determine whether a specific monocyte subset occurred more often in patients with dementia. We also studied whether soluble products from a monocyte subset caused neural-cell death in vitro.

Section snippets

Blood samples

Individuals with AIDS dementia were recruited from St Mary's Medical Center Dementia Ward (San Francisco), and clinics of the University of California, San Francisco. Exclusion criteria included history of head injury, seizures, or multiple sclerosis, active opportunistic infection, active opportunistic central-nervous system infection or lymphoma, cerebrovascular disease, major psychiatric illness, other known causes of dementia, or pre-existing cause of brain disorder. Participants or their

Results

Forward-angle light-scatter analysis between the various populations of monocytes was similar, suggesting that the overall size of the monocytes between the various groups was the same. However, with side-scatter analysis, there was a significant increase in scatter among monocytes from patients with AIDS dementia compared with non-demented AIDS patients (p=0·001) (data not shown). Most cells from patients with dementia had side-scatter histograms over 1000.

To study whether the monocytes with

Discussion

Investigators have looked in the cerebrospinal fluid and serum for markers of immune activation specific for HIV neurological involvement, such as neopterin, β₂-microglobulin, and quinolinic acid. These three are elevated in HIV encephalitis, although none showed a strong correlation with severity of HIV neurological involvement.²⁰ Quinolinic acid is increased in the cerebrospinal fluid and serum of patients with HIV infection and neurological involvement.²¹ Neopterin and β₂-microglobulin are

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Early ReportUnique monocyte subset in patients with AIDS dementia

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Blood samples

Results

Discussion

Virology

Blood

Blood

Blood

J Neuroimmunol

Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections

Ann Neurol

Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlation with dementia

Ann Neurol

Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1

Science

Human immunodeficiency virus-infected macrophages produced soluble factors that cause histological and neurochemical alterations in cultured human brain

J Clin Invest

Interleukin-1 and tumor necrosis factor α can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor

J Virol

Induction of interleukin-1 and tumor necrosis factor α in brain cultures by human immunodeficiency virus type 1

J Virol

Cytokines and arachidonic acid metabolites produced during HIV-infected macrophage-astroglial interactions: implications for the neuropathogenesis of HIV disease

J Exp Med

Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin

J Virol

The regulation of quinolinic acid in human immunodeficiency virus-infected monocytes

J Neurol Virol

Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid

Biochem J

Early Report
Unique monocyte subset in patients with AIDS dementia