Abstract
HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients.In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury.Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.
Highlights
History The AIDS dementia complex (ADC) or HIV-associated dementia (HAD) was recognized as a novel central nervous system (CNS) disorder early in the AIDS epidemic [1] and subsequently linked to a pathological substrate of HIV encephalitis (HIVE) [2]
cerebrospinal fluid (CSF) Neopterin Across the Spectrum of HIV Infection To provide a view of the CSF neopterin changes across the spectrum of HIV infection and HIV-related CNS injury within the context of other biomarkers, we examined a cross-sectional sample derived from four clinical centers that included HIV seronegative subjects, untreated neuroasymptomatic HIV-infected subjects grouped according to blood CD4+ T cell, ADC neurological diagnoses, two groups of treated HIV-patients and five groups with CNS opportunistic diseases
Combination antiretroviral drug treatment has had a dramatic effect on morbidity and mortality of HIV infection, including those involving the CNS and the previously most common of these, ADC/HIVE
Summary
History The AIDS dementia complex (ADC) or HIV-associated dementia (HAD) was recognized as a novel central nervous system (CNS) disorder early in the AIDS epidemic [1] and subsequently linked to a pathological substrate of HIV encephalitis (HIVE) [2]. Patient B was 47 years when diagnosed with ADC Stage 2 in January, 2000, again with a substantially higher CSF than blood neopterin level Dementia was his presenting manifestation of HIV infection and the blood CD4+ T cell count was 130 cells per μL The CSF neopterin response was a little slower in the previous case when he was treated with ritonavirboosted indinavir, zidovudine and lamivudine. The final patient (D) illustrates a steady rise in CSF neopterin that was dissociated from his relatively stable blood neopterin, proportionally exceeded his log CSF HIV RNA increase and preceded his clinical presentation This suggests an increase in CNS infection, but a switch in its character to a type that associates with brain injury.
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