Neurological complications of HIV infection

doi:10.1016/S1474-4422(05)70165-4

The Lancet Neurology

Volume 4, Issue 9, September 2005, Pages 543-555

https://doi.org/10.1016/S1474-4422(05)70165-4 Get rights and content

Summary

Cognitive disorders, vacuolar myelopathy, and sensory neuropathies associated with HIV are the most common disorders in patients with HIV AIDS, and are the focus of this review. These disorders are treatable and of those associated with HIV AIDS the pathogenic mechanisms are the most understood. Although triggered by productive HIV macrophage infections, aberrant immune activation plays a major role in inducing the CNS disorders. Novel therapies aimed at these inflammatory mechanisms can be effective. The sensory neuropathies associated with HIV infection are a major cause of morbidity; incidence may be increased by the toxic effects of specific antiretroviral drugs within the peripheral nervous system.

Section snippets

Biology of HIV infection

HIV-1 is a retrovirus that produces profound CD4 depletion, possibly through an initial massive depletion of gut-associated memory T cells, and then chronic immune activation, leading to fatigue of homoeostatic T-cell responses and progressive immunodeficiency. The CD4 receptor is the main target for HIV-1, however, specific chemokine receptors are important secondary cellular receptors.1, 2 Additionally, specific lectins on dendritic cells may stabilise HIV for presentation to susceptible

Neurological symptoms of HIV infection

HIV may affect the nervous system directly, producing distinct neurological syndromes, or indirectly, by causing immunodeficiency with a resultant susceptibility to opportunistic infections. Nervous system infection with HIV-1 can produce a range of clinical disorders, but only dementia, myelopathy, and sensory neuropathies will be discussed here. These debilitating disorders generally do not develop until advanced stages of HIV infection. Typically, other AIDS-defining illnesses or

Epidemiology

HIV-D, also called HIV encephalopathy and AIDS dementia complex, rarely develops before profound immunosuppression. The lifetime prevalence of HIV-D in a group of 5000 homosexual men in the USA was about 15%,¹² but may be different in other populations. Risk factors include high HIV set point early in HIV infection, low CD4 counts,¹³ anaemia, low body-mass index, age (risk increases with increasing age), systemic symptoms,¹² injection-drug use,¹⁴ and female sex.¹⁵ In cohort studies of patients

HIV-1-associated myelopathies

Vacuolar myelopathy (VM) is the myelopathy most commonly associated with HIV-1; it is a slowly progressive painless spastic paraparesis, with sensory ataxia and neurogenic bladder, characterised by prominent vacuolar changes in the ascending and descending tracts that particularly affect the thoracic spinal cord. VM is symptomatic in 5–10% of patients with AIDS, but has been identified pathologically in almost 50% of cases at autopsy.¹⁰⁷ This myelopathy commonly parallels the development of

Sensory neuropathies associated with HIV

The peripheral nervous system may be involved in diverse ways. Several diagnoses, which might be immune-mediated, have been described, such as cranial neuropathies, polymyositis, motor-neuron disease, and inflammatory demyelinating polyneuropathies; these are discussed elsewhere.114, 115

Conclusion

AIDS has caused 20 million deaths, and it is estimated that almost 38 million people worldwide are infected with HIV. The range of neurological disorders associated with HIV AIDS continues to increase, and HIV-D and HIV-SN will increase in prevalence as use of HAART increases, survival lengthens, and there are more people living with HIV. Generic antiretrovirals in resource-limited countries commonly contain neurotoxic nucleoside analogues, such as d4T, and the lengthy exposure to these

Search strategy and selection criteria

We searched PubMed from 1986 to March 2005 for “HIV-associated dementia”, “vacuolar myelopathy” or “sensory neuropathies”.

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We completed a cross-sectional survey study to determine headache prevalence and its association with HIV characteristics among people living with HIV (PLHIV) in Lusaka, Zambia.
Headaches are common but their association with HIV status is unknown.
The HARDSHIP survey, a headache epidemiology questionnaire previously validated in Zambia, was distributed during a 3-month period to 3666 consecutive adult PLHIV attending routine clinic appointments at the Adult Infectious Diseases Centre at the University Teaching Hospital in Lusaka, Zambia. HIV disease characteristics were abstracted from their charts.
1015 (27.7%) participants responded to the survey. Adjusted for age, 64% reported having a headache within the last year unrelated to another illness. Among participants, 201 met criteria for migraine (20%), 259 for tension-type headache (26%), 18 for probable medication-overuse headache (2%), and 121 for undetermined headache (12%). Prevalence for tension-type headache was significantly higher than that of migraine (P < 0.001). After adjusting for age and sex, higher CD4 counts were associated with migraine. No other associations were observed between overall headache or headache type with HIV disease characteristics including CD4 count, viral load, antiretroviral regimen, and time since HIV diagnosis.
Headaches are highly prevalent among this cohort of PLHIV in Zambia. Optimizing headache treatment and integrating it into routine HIV care may improve quality of life for a substantial proportion of PLHIV in Zambia.
Antiretroviral therapy and its cerebral vascular toxicity
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Infection by human immunodeficiency virus-1 (HIV) once had a near-certainly fatal prognosis. Today, HIV infection can be controlled due to the advent and deployment of antiretroviral therapy (ART), allowing HIV-infected (HIV+) patients to survive longer. HIV+ patients frequently experience comorbidities that stem, at least in part, from side effects induced by the long-term use of ART. HIV+ patients commonly exhibit microvascular alterations and disruptions of the blood–brain barrier (BBB), which may be caused or exacerbated by ART-induced toxicity. The BBB, being the crucial anatomic and biochemical interface between peripheral circulation and the central nervous system, is particularly exposed to potentially toxic effects of antiretroviral drugs (ARVds). This chapter analyzes the adverse effects related to the therapeutic use of ARVds in the context of BBB dysfunction and ART-induced toxicity. Moreover, it provides possible future approaches to HIV therapy, which may mitigate the toxicities observed in ART-treated patients.
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Nucleoporin Seh1 maintains Schwann cell homeostasis by regulating genome stability and necroptosis
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Schwann cells play critical roles in peripheral neuropathies; however, the regulatory mechanisms of their homeostasis remain largely unknown. Here, we show that nucleoporin Seh1, a component of nuclear pore complex, is important for Schwann cell homeostasis. Expression of Seh1 decreases as mice age. Loss of Seh1 leads to activated immune responses and cell necroptosis. Mice with depletion of Seh1 in Schwann cell lineage develop progressive reduction of Schwann cells in sciatic nerves, predominantly non-myelinating Schwann cells, followed by neural fiber degeneration and malfunction of the sensory and motor system. Mechanistically, Seh1 safeguards genome stability by mediating the interaction between SETDB1 and KAP1. The disrupted interaction after ablation of Seh1 derepresses endogenous retroviruses, which triggers ZBP1-dependent necroptosis in Schwann cells. Collectively, our results demonstrate that Seh1 is required for Schwann cell homeostasis by maintaining genome integrity and suggest that decrease of nucleoporins may participate in the pathogenesis of periphery neuropathies.
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ReviewNeurological complications of HIV infection

Summary

Section snippets

Biology of HIV infection

Neurological symptoms of HIV infection

Epidemiology

HIV-1-associated myelopathies

Sensory neuropathies associated with HIV

Conclusion

Search strategy and selection criteria

Cell

J Neurol Sci

J Neuroimmunol

J Neuroimmunol

Hum Pathol

J Neuroimmunol

Exp Neurol

Prog Neurobiology

J Biol Chem

Virology

CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia

Nature

Chemokine receptors—gateways to inflammation and infection

Nat Med

Viral DNA and mRNA expression correlate with the stage of human immunodeficiency virus (HIV) type 1 infection in humans: evidence for viral replication in all stages of HIV disease

J Virol

Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection

Nature

Use of HIV viral load in clinical practice: back to the future

Ann Intern Med

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy

Science

Targeting neurotherapeutic agents through the blood-brain barrier

Arch Neurol

Recovery of replication-competent HIV despite prolonged suppression of plasma viremia

Science

HIV infection and dementia

Science

A unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy

J AIDS

Dementia in AIDS patients: incidence and risk factors

Neurology

Plasma viral load and CD4 lympocytes predict HIV-associated dementia and sensory neuropathy

Neurology

Epidemiology of human immunodeficiency virus encephalopathy in the United States

Neurology

Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia

Neurology

The impact of zidovudine on dementia-free survival in a population of HIV-positive men and women on antiretroviral therapy

Int J STD AIDS

Circulating proviral HIV DNA and HIV-associated dementia

AIDS

Dysregulation of sphingolipid and sterol metabolism by ApoE4 in HIV dementia

Neurology

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

Nat Med

HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels

Proc Natl Acad Sci USA

Increased frequency of the tumor necrosis factor-alpha-308 A allele in adults with human immunodeficiency virus dementia

Ann Neurol

Human immunodeficiency virus (HIV) infection and the nervous system: report from the American Academy of Neurology AIDS Task Force

Neurology

The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy

J Neurovirol

Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity

Neurology

Mortality risks in gay men with human immunodeficiency virus infection and cognitive impairment

Neurology

Psychomotor slowing in HIV infection: a predictor of dementia, AIDS, and death

J Neurovirol

Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis

Neurology

Pediatric acquired immunodeficiency syndrome: neurologic syndromes

Am J Dis Child

Progressive encephalopathy in children with acquired immune deficiency syndrome

Ann Neurol

Elevated serum levels of tumor necrosis factor are associated with progressive encephalopathy in children with acquired immunodeficiency syndrome

Am J Dis Child

Low blood CD8+ T-lymphocytes and high circulating monocytes are predictors of HIV-1-associated progressive encephalopathy in children

Pediatrics

Review
Neurological complications of HIV infection