The neuropathogenesis of HIV-1 infection of the central nervous system (CNS) has been
intensively studied, yet it remains incompletely understood. The virus enters the
CNS early after systemic infection, establishes a viral reservoir, and remains largely
inaccessible to antiretroviral therapies. In certain individuals, slowly evolving
cognitive dysfunction becomes manifested years after infection, resulting in frank
dementia (AIDS dementia complex [ADC]) in approximately 10% of individuals, with less
severe cognitive dysfunction in up to 50% of all infected individuals. Neuropathologic
and neuroimaging studies demonstrate that reversible metabolic disturbances occur
in neurons and glia early after CNS invasion and that progressive, irreversible neurodegeneration
may precede overt clinical deterioration by years. In vitro studies demonstrate that
HIV-1 infection of macrophages and microglia, the endogenous brain macrophages, releases
soluble factors that induce neuronal cell death. The viral and host factors that modulate
neuronal cell death in vivo are only partly understood. Evolving therapies directed
toward preventing neurodegeneration in HIV infection include CNS-penetrating antiretroviral
drugs and pharmacologic agents that protect neurons from effects of HIV-1–infected
macrophage neurotoxins. Major unanswered questions concerning the pathogenesis and
prevention of HIV-1–induced CNS degeneration include (1) which cellular and viral
factors are primarily responsible for HIV-1–induced neurodegeneration in vivo; (2)
which surrogate markers of HIV-1 infection in the CNS (eg, viral load or cytokines)
can predict risk for neurodegeneration; and (3) can antiretroviral drugs or specific
CNS-targeted agents protect against HIV-1?
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.
Content published before 2002 is available via pay-per-view purchase only.
Subscribe:
Subscribe to Clinics in Laboratory MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The neuropathogenesis of HIV-1 infection.J Leukoc Biol. 1994; 56: 389
- Dementia associated with the acquired immunodeficiency syndrome.N Engl J Med. 1995; 332: 934
- The effects of human immunodeficiency virus in the central nervous system.Adv Virus Res. 1998; 50: 1
- Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients.Proc Natl Acad Sci USA. 1986; 83: 7089
- Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy.Science. 1986; 233: 1089
- Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS.J Exp Med. 2001; 193: 905
- Clinical-neuropathological correlation in HIV-associated dementia.Neurology. 1993; 43: 2230
- Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia.Ann Neurol. 1995; 38: 755
- Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome.N Engl J Med. 1985; 313: 1493
- Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain.Ann Neurol. 1997; 42: 689
- Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy.Neurology. 1999; 52: 607
- HIV-1 RNA levels in cerebrospinal fluid and plasma correlate with AIDS dementia.AIDS. 1998; 12: 818
- Neurological disorders during HIV-1 infection correlate with viral load in cerebrospinal fluid but not with virus phenotype.AIDS. 1998; 12: 737
- Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage.J Infect Dis. 1997; 175: 963
- The level of human immunodeficiency virus (HIV) type 1 RNA in cerebrospinal fluid as a marker of HIV encephalitis.Clin Infect Dis. 1998; 26: 1072
- Evidence of apoptotic cell death in HIV encephalitis.Am J Pathol. 1995; 146: 1121
- Expression of pro- and anti-apoptosis gene products in brains from paediatric patients with HIV-1 encephalitis.Neuropathol Appl Neurobiol. 1997; 23: 242
- Apoptosis induced by HIV-1 infection of the central nervous system.J Clin Invest. 1996; 98: 1979
- Neuronal apoptosis in HIV infection in adults.Neuropathol Appl Neurobiol. 1995; 21: 218
- Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage.Neuropathol Appl Neurobiol. 1999; 25: 123
- Programmed cell death in brains of HIV-1-positive AIDS and pre-AIDS patients.Acta Neuropathol (Berl). 1996; 91: 169
- Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy.Neuropathol Appl Neurobiol. 1995; 21: 208
- HIV-associated neuropathology.in: Gendelman H.E. Lipton S.A. Epstein L. Swindells S. The Neurology of AIDS. Chapman & Hall, New York2001: 241
- Pathology of HIV-1 infection of the central nervous system. A review.J Neuropathol Exp Neurol. 1992; 51: 3
- Microglia in human disease, with an emphasis on acquired immune deficiency syndrome.Lab Invest. 1991; 64: 135
- Pathways to neuronal injury and apoptosis in HIV-associated dementia.Nature. 2001; 410: 988
- Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia.Ann Neurol. 2001; 49: 745
- Isolates of human immunodeficiency virus type 1 from the brain may constitute a special group of the AIDS virus.Proc Natl Acad Sci USA. 1989; 86: 8575
- Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity.J Virol. 2001; 75: 10073
- HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC–CKR-5.Nature. 1996; 381: 667
- CXCR-4 is expressed by primary macrophages and supports CCR5-independent infection by dual-tropic but not T-tropic isolates of human immunodeficiency virus type 1.J Virol. 1997; 72: 772
- In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression.Nat Med. 1997; 3: 1259
- Varied tropism of HIV-1 isolates derived from different regions of adult brain cortex discriminate between patients with and without AIDS dementia complex (ADC): evidence for neurotopic HIV variants.Virology. 2001; 279: 509
- HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies.Virology. 1991; 180: 583
- Distinct populations of human immunodeficiency virus type 1 in blood and cerebrospinal fluid.AIDS Res Hum Retroviruses. 1992; 8: 53
- Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies.AIDS Res Hum Retroviruses. 1998; 14: 25
- Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences.J Virol. 1994; 68: 4643
- Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences.J Virol. 1994; 68: 7467
- Differences in human immunodeficiency virus type 1 V3 sequences from patients with and without AIDS dementia complex.J Gen Virol. 1995; 76: 175
- The HIV Neurobehavioral Research Group: sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis.AIDS Res Hum Retroviruses. 1996; 12: 477
- HIV type 1 V3 sequences and the development of dementia during AIDS.AIDS Res Hum Retroviruses. 1996; 12: 471
- Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope.J Virol. 1999; 73: 897
- Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate.J virol. 2002; 76: 6277
- Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients.J Virol. 1998; 72: 9045
- Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4.Curr Biol. 1998; 8: 595
- Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis: implications for human immunodeficiency virus type 1-associated dementia.J Virol. 1999; 73: 8256
- Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia.J Neuroimmunol. 1999; 98: 185
- Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis.Neuropathol Appl Neurobiol. 1999; 25: 380
- Up-regulation of bax protein levels in neurons following cerebral ischemia.J Neurosci. 1995; 15: 6364
- Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons.Ann Neurol. 1997; 42: 847
- Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclearphagocytes found in human brain.J Neurosci. 1996; 16: 3139
- Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine.Ann Neurol. 2000; 47: 186
- Models of neuronal injury in AIDS: another role for the NMDA receptor?.Trends Neurosci. 1992; 15: 75
- Memantine prevents HIV coat protein-induced neuronal injury in vivo.Neurology. 1992; 42: 1403
- Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity.Neuron. 1991; 7: 111
- Involvement of activated caspase-3-like proteases in N-methyl-d-aspartate-induced apoptosis in cerebrocortical neurons.J Neurochem. 2000; 74: 134
- Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.Proc Natl Acad Sci USA. 1991; 88: 6368
- Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures.Proc Natl Acad Sci USA. 1993; 90: 3256
- Reactive nitrogen intermediates in human neuropathology: an overview.Dev Neurosci. 1994; 16: 152
- Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide.Nature. 1988; 335: 639
- gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-1.J Neurosci. 1996; 16: 4080
- HIV-1 envelope proteins gp120 and gp160 potentiate NMDA-induced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons.Eur J Neurosci. 1995; 7: 2285
- Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis.Proc Natl Acad Sci USA. 1999; 96: 8212
- Increased frequency of the tumor necrosis factor-308 A allele in adults with human immunodeficiency virus dementia.Ann Neurol. 2001; 50: 157
- Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis.Dev Neurosci. 1993; 15: 417
- In vitro evidence for a dual role of tumor necrosis factor-α in human immunodeficiency virus type 1 encephalopathy.Ann Neurol. 1995; 37: 381
- Up-regulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection.Acta Neuropathol. 1999; 98: 355
- Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines.J Exp Med. 1998; 188: 83
- Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy.Proc Natl Acad Sci USA. 1997; 94: 13193
- Residual HIV-1 disease in the era of highly active antiretroviral therapy.N Engl J Med. 1999; 40: 1672
- Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection.Proc Natl Acad Sci USA. 1998; 95: 8869
- Latent reservoirs of HIV: obstacles to the eradication of virus.Proc Natl Acad Sci USA. 1999; 96: 10958
- Restoration of the immune system with anti-retroviral therapy.Immunol Lett. 1999; 66: 207
- AIDS Clinical Trials Group: zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial.Ann Neurol. 1993; 33: 343
- Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection.N Engl J Med. 1988; 319: 889
- Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex.AIDS. 1993; 7: 683
- Antiretroviral drugs and the central nervous system.AIDS. 1998; 12: 1941
- Highly active antiretroviral therapy reverse brain metabolite abnormalities in mild HIV dementia.Neurology. 1999; 53: 782
- Suppression of inflammatory neurotoxins by highly active antiretroviral therapy in human immunodeficiency virus-associated dementia.J Infect Dis. 1998; 178: 1000
- Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection.Neurology. 1991; 41: 778
- Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS).Neurology. 1999; 12: 1640
- Changes to AIDS dementia complex in the era of highly active antiretroviral therapy.AIDS. 1999; 13: 1249
- Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources.Neurology. 2000; 54: 927
- The AIDS Clinical Trials Group: A phase I/II trial of nimodipine for HIV-related neurologic complications.Neurology. 1998; 51: 221
- Human immunodeficiency virus-associated dementia.Arch Neurol. 2000; 57: 321
- Neuronal injury associated with HIV-1: approaches to treatment.Annu Rev Pharmacol Toxicol. 1998; 38: 159
- Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1.Science. 1990; 250: 1593
- Mechanisms and structural determinants of HIV-1 coat protein, gp41-induced neurotoxicity.J Neurosci. 1999; 19: 64
- Immunologic NO synthase: elevation in severe AIDS dementia and induction by gp41.Science. 1996; 274: 1917
- Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study.Neurology. 2000; 54: 233
- Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival.Proc Natl Acad Sci USA. 2000; 97: 8075
- Akt/protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria.Mol Cell Biol. 1999; 19: 5800
Article info
Footnotes
☆This work is supported by grants NS37651 and NS27405 from the National Institutes of Health.
Identification
Copyright
© 2002 Elsevier Science (USA). Published by Elsevier Inc. All rights reserved.
