On cerebrospinal fluid markers of HIV-1 infection

Abstract

HIV-1 infects the central nervous system early in the course of infection and neurological complications are common in HIV-1-infected individuals. Approximately 20% of individuals with acquired immunodeficiency syndrome (AIDS) not treated with antiretroviral therapy develop a subcortical dementia, AIDS dementia complex (ADC). The pathological pathways that lead to nerve cell injury in HIV-1 infection are not fully understood. Antiretroviral therapy has lowered the incidence of opportunistic infections and tumours in HIV-1 infection but the impact on ADC is less clear.The ganglioside GD3 (GD3) is expressed by activated microglia and reactive astroglia in the adult brain. Glial fibrillary acidic protein (GFAp) is an astrocyte marker. We have analysed cerebrospinal fluid (CSF) levels of GD3 and GFAp in 22 neuroasymptomatic HIV-1 infected individuals and 44 age-matched HIV-negative controls. The mean CSF GD3 level was higher in HIV-1 infected individuals than in controls. Six HIV-1-infected individuals had elevated CSF GD3 concentrations but normal GFAp levels indicating microglial activation early in the course of infection in some patients.To study a marker of axonal degeneration in HIV-1 infection, we measured CSF protein tau (tau) in 37 neuroasymtomatic HIV-1 infected individuals, 8 patients with ADC, 7 HIV-1 infected patients with other CNS opportunistic infections or tumours, and 42 age-matched HIV-negative controls. CSF tau levels were elevated in patients with ADC and other CNS opportunistic infections or tumours compared to neuroasymptomatic HIV-1 infected individuals and controls. CSF tau might be used as a marker of axonal degeneration but it cannot discriminate between ADC and other CNS opportunistic infections or tumours in HIV-1 infection.HIV-1 infection of the CNS triggers a cellular immune response that can be measured as elevated CSF neopterin concentrations and disruption of the blood-brain barrier is a common finding in HIV-1 infection. To investigate the relationship between intrathecal immune activation and disruption of the blood-brain barrier, we analysed CSF and serum neopterin, CSF and plasma HIV-1 RNA, CSF mononuclear cell count, and albumin ratio in 110 neuroasymptomatic HIV-1-infected individuals without antiretroviral treatment. The albumin ratio was correlated to the CSF and serum neopterin concentrations and to the CSF HIV-1 RNA levels but not to the plasma HIV-1 RNA levels, indicating that cellular immune activation, and possibly, intrathecal HIV-1 virus replication, are factors associated with increased blood-brain barrier permeability in neuroasymptomatic HIV-1-infected individuals.HIV-1 can be isolated from blood from almost all HIV-1-infected individuals not treated with antiretroviral therapy. Isolation rates from CSF, however, are considerably lower, ranging from 20 to 70%. We examined 303 CSF samples and 278 paired blood samples from 157 HIV-1 seropositive patients in all stages of the disease to evaluate HIV-1 RNA levels in CSF and blood as a predictor of culturability and to estimate a cut-off level above which the positive predictive value for positive virus isolation was =90%. While HIV-1 was isolated from the vast majority of blood samples with HIV-1 RNA levels just above the detection limit of the assay (>200 copies/mL), a cut-off level of >5000 HIV-1 RNA copies/mL was required to yield a positive predictive value =90% for virus isolation from CSF samples.