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The neuropathogenesis of AIDS

Nature Reviews Immunology volume 5, pages 69–81 (2005)Cite this article

Key Points

  • The incidence of HIV-associated dementia has decreased since patients have been treated with highly active antiretroviral therapy (HAART); however, the prevalence of cognitive disorders remains high, owing to the longer lifespan (and concomitantly greater average age) of patients who are infected with HIV and to the appearance of less-severe disorders of cognition in treated patients.

  • Most of the HIV entering the brain does so within infected monocytes that cross the blood–brain barrier to replenish the population of perivascular macrophages. HIV might reside in the brain for long periods, forming a separate genetic subgroup in an infected patient.

  • Most, if not all, of the virus being produced in the brain is from macrophages and microglia, because infection of astrocytes, although it occurs, does not lead to high levels of virus production. Multinucleated giant cells, the hallmark neuropathology of HIV infection, are formed by the fusion of infected and uninfected macrophages and microglia.

  • Neuronal apoptosis is a key neuropathological consequence of HIV infection; it might be mediated by the effects of infected, activated macrophages and microglia, possibly with a direct contribution from viral proteins that interact with cell-surface receptors on macrophages, or even more directly, on neurons.

  • The brains of individuals who are infected with HIV have altered expression of both chemokines and chemokine receptors. The balance between the roles of chemokines as potentially neurotoxic and neuroprotective has not yet been fully elucidated.

  • Potential neuroprotective therapies, other than treatment with antiretroviral drugs, are targeted to interrupt direct damage to neurons by blunting the effects of macrophage activation and infection.

Abstract

HIV-associated dementia (HAD) is an important complication of the central nervous system in patients who are infected with HIV-1. Although the incidence of HAD has markedly decreased since it has become possible to effectively control viral replication in the blood by administering highly active antiretroviral therapy, a less severe form of HAD, comprising a milder cognitive and motor disorder, is now potentially a serious problem. Brain macrophages and microglia are the key cell types that are infected by HIV-1 in the central nervous system, and they are likely to mediate the neurodegeneration seen in patients with HAD; however, the precise pathogenesis of this neurodegeneration is still unclear. Here, we discuss the studies that are being carried out to determine the respective contributions of infection, and monocyte and macrophage activation, to disease progression.

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Figure 1: The location of different cell types in the brain.
Figure 2: HIV neuroinvasion and multinucleated giant-cell formation.
Figure 3: Mechanisms of neurodegeneration and neuroprotection in AIDS.

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Acknowledgements

We are supported by grants from the National Institute of Neurological Disorders and Stroke (United States) and the National Institute of Mental Health (United States). We regret that space constraints prevented the inclusion of important findings by many of our colleagues.

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Authors and Affiliations

  1. Department of Neurology, 3 West Gates, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, 19104-4283, Philadelphia, USA

    Francisco González-Scarano & Julio Martín-García

  2. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6076, Philadelphia, USA

    Francisco González-Scarano

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  1. Francisco González-Scarano
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Correspondence to Francisco González-Scarano.

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DATABASES

Entrez Gene

CCR5

CD4

CX3CL1

CXCL12

CXCR4

gp120

Tat

TNF

Vpr

Infectious Disease Information

AIDS

Glossary

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

(HAART). Aggressive anti-HIV combination therapy that includes three or more protease and reverse-transcriptase inhibitors.

INCIDENCE

Number of new cases of a particular disease per year per group of population.

PREVALENCE

Percentage or proportion of a population that is affected by a particular disease at a given time.

MULTIPLE SCLEROSIS

Neurodegenerative disorder that is characterized by demyelination of bundles of nerve fibres in the central nervous system. Symptoms depend on the site of the lesion but include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.

ALZHEIMER'S DISEASE

Degenerative mental disease that is characterized by progressive brain deterioration and dementia, and by the presence of senile plaques, neurofibrillary tangles and neuropil threads. Disease onset can occur at any age, and women seem to be affected more frequently than men.

BLOOD–BRAIN BARRIER

Selectively permeable cellular layer formed by brain microvascular endothelial cells, which are linked by tight junctions. It is crucial for the maintenance of homeostasis in the brain environment.

CHOROID PLEXUS

Site of production of cerebrospinal fluid in the adult brain. It is formed by invagination of ependymal cells into the ventricles, which become highly vascularized.

TRANSCYTOSIS

Process of transport of material across an epithelial layer by uptake on one side of the epithelial cell into a coated vesicle that might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

MESODERM

Middle of the three germ layers of the embryo. It gives rise to the blood, to the musculoskeletal, circulatory and urogenital systems, and to the connective tissue (including that of dermis), and it contributes to some glands.

ECTODERM

Outer of the three germ layers of the embryo. It gives rise to the epidermis and most of the neural tissue.

MONONUCLEAR PHAGOCYTIC SYSTEM

Group of bone-marrow-derived cells with different morphologies (monocytes, macrophages and dendritic cells), which are mainly responsible for phagocytosis, cytokine secretion and antigen presentation.

MENINGES

Surrounding membranes of the brain and spinal cord. There are three layers of meninges: the dura mater (outer), the arachnoid membrane (middle) and the pia mater (inner).

MULTINUCLEATED GIANT CELLS

(MNGCs). Conglomerates of cells that form through the fusion of infected and uninfected macrophages and microglia. The fusion is mediated by HIV-envelope glycoproteins present at the surface of infected cells and CD4 and chemokine receptors at the surface of uninfected cells. MNGCs are the pathological hallmark of HIV neuropathology.

N-METHYL-D-ASPARTATE

(NMDA). Amino-acid derivative that functions as a specific agonist of the NMDA receptor and therefore mimics the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, it binds and opens only the NMDA receptor and not other glutamate receptors.

PRE-INTEGRATION COMPLEX

Ensemble of the viral RNA genome that is present in the virion (which consists of the nucleocapsid protein, the structural protein p6, the accessory protein Vpr, the integrase protein and several copies of the matrix protein), where the synthesis of viral DNA occurs. By engaging cellular proteins, the viral DNA can then be transported to the nucleus, where it can be integrated into the genome of the host cell.

MATRIX METALLOPROTEINASES

Peptide hydrolases that use a metal for their catalytic mechanism and degrade the extracellular matrix. They have an important role in several neurodegenerative processes.

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González-Scarano, F., Martín-García, J. The neuropathogenesis of AIDS. Nat Rev Immunol 5, 69–81 (2005). https://doi.org/10.1038/nri1527

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