Cerebrospinal Fluid Of HIV-infected Patients Research Articles

Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome.

Background. Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood.Methods. We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10).Results. At diagnosis, highly activated CD8+ T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4+ T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood.Conclusions. After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4+ T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS.

Detection of High Cerebrospinal Fluid Levels of (1→3)-β-d-Glucan in Cryptococcal Meningitis.

(1→3)-β-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis. The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality. The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200-597) pg/mL in cryptococcal patients and 37 (23-46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were ≥10 000 colony-forming units/mL. (1→3)-β-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG ≥500 pg/mL at diagnosis was associated with increased 10-week mortality. (1→3)-β-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes.

Hepatitis B virus compartmentalization in the cerebrospinal fluid of HIV-infected patients

We detected hepatitis B virus (HBV) DNA in the cerebrospinal fluid (CSF) of 26 adolescents co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) with neurological disease and studied compartmentalization of HBV in the CSF. More than half of the subjects with positive HBV DNA plasma also had CSF positive for HBV. CSF HBV DNA was found in subjects with preserved blood–brain barrier integrity. In a subgroup of these subjects, compartmentalized evolution of HBV was demonstrated by distinct profiles of resistance mutations. Future studies are warranted to determine the clinical significance of HBV presence in the CSF and its contribution to HIV-associated neurological disease.

HIV-1 Vpr activates the NLRP3 inflammasome in primary human microglia

Human immunodeficiency virus type 1 (HIV-1) infects microglia and macrophages in the brain during seroconversion and eventually results in neuroinflammation and neurodegeneration in susceptible individuals. Inflammasomes are cytosolic protein complexes that serve as platforms for caspase-1 activation and ensuing cleavage and release of IL-1beta and IL-18. Our group recently showed that HIV-1 infection of human microglia induces the NLRP3 inflammasome. The viral protein R (Vpr) is an accessory protein encoded by HIV-1, which is essential for macrophage infection and is detected in serum and cerebrospinal fluid of HIV-infected patients.

Differential polarization between resident microglia and brain infiltrating macrophages in mouse models of Alzheimer's disease

Human immunodeficiency virus type 1 (HIV-1) infects microglia and macrophages in the brain during seroconversion and eventually results in neuroinflammation and neurodegeneration in susceptible individuals. Inflammasomes are cytosolic protein complexes that serve as platforms for caspase-1 activation and ensuing cleavage and release of IL-1beta and IL-18. Our group recently showed that HIV-1 infection of human microglia induces the NLRP3 inflammasome. The viral protein R (Vpr) is an accessory protein encoded by HIV-1, which is essential for macrophage infection and is detected in serum and cerebrospinal fluid of HIV-infected patients. We investigated the actions of extracellular and intracellular Vpr expression on inflammasome activation in cells of monocytic lineage. Extracellular Vpr exposure to differentiated human monocytic cells (THP-1) and primary human microglia caused caspase-1 activation and reduced cell viability (p b 0.01). Vpr exposure also significantly increased transcription and secretion of IL-1beta and IL-18 (p b 0.001) although this effect was eliminated in THP-1 cells deficient in NLRP3. Infection of THP-1s and microglia with HIV-1 HxBruR−E+ (Vprdeficient) showed significantly reduced caspase-1 activation and IL1beta production (p b 0.01) compared to cells infected with HIV-1 HxBruRE (Vpr-encoding). To examine the effects of intracellular Vpr expression on inflammasome activation, THP-1 cells were transfected with Vpr, revealing enhanced caspase-1 activation and reduced cellular viability (p b 0.001) but without significant IL-1beta release. These observations indicated that extracellular Vpr activates the NLRP3 inflammasome by acting as both Signals 1 and 2. Thus, Vpr-induced NLRP3 inflammasome activation likely contributes to HIV-1 associated neuroinflammation.

Evidence for cFMS signaling in HIV production by brain macrophages and microglia

Combination antiretroviral therapy (cART) has improved the longevity and quality of life for people living with HIV; however, it does not target virus that persists in long-lived cells, such as macrophages (MΦs). This allows for the development of viral reservoirs in various anatomical compartments where these cells reside, including the central nervous system (CNS), where perivascular MΦs and resident microglia constitute the principle cellular reservoir of HIV. How HIV persists in MΦs/microglia is not completely understood; however, prosurvival signaling that protects infected MΦs/microglia from apoptosis is likely important to viral persistence. Macrophage colony-stimulating factor (M-CSF) is an important factor in MΦ survival and has been implicated in HIV neuropathogenesis through its ability to enhance the susceptibility of MΦs to infection and promote virus production. While M-CSF has been detected in cerebrospinal fluid of HIV-infected patients, the cellular source of M-CSF in the CNS is unknown. Here, we demonstrate, for the first time, that MΦs comprising perivascular cuffs and nodular lesions in SIV encephalitis (SIVE) brain are the principle source of M-CSF. These cells also serve as the primary reservoir of productive SIV infection in the brain. We further demonstrate that M-CSF and IL-34, which signal through the same receptor, cFMS, enhance HIV-1 production by microglia in vitro. This is attenuated by the addition of a receptor tyrosine kinase inhibitor with high specificity for cFMS, GW2580. Together, these data suggest that cFMS signaling may be an attractive target for eliminating long-lived MΦ reservoirs of HIV in the brain and other tissues.

Polimorfismos en los genes dihidrofolatorreductasa (dhfr) y dihidropteroatosintetasa (dhps) y modelamiento estructural del gen dhps en aislamientos colombianos de Toxoplasma gondii

There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates.This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii .Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced.One polymorphism (A « G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G « C) at positions 259 and 260 and one polymorphism (T « G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations.The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response.

Gene polymorphisms in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) genes and structural modelling of the dhps gene in Colombian isolates of Toxoplasma gondii

There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates. This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii . Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced. One polymorphism (A « G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G « C) at positions 259 and 260 and one polymorphism (T « G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations. The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response.

HIV-1-Tat excites cardiac parasympathetic neurons of nucleus ambiguus and triggers prolonged bradycardia in conscious rats

The mechanisms of autonomic imbalance and subsequent cardiovascular manifestations in HIV-1-infected patients are poorly understood. We report here that HIV-1 transactivator of transcription (Tat, fragment 1-86) produced a concentration-dependent increase in cytosolic Ca(2+) in cardiac-projecting parasympathetic neurons of nucleus ambiguus retrogradely labeled with rhodamine. Using store-specific pharmacological agents, we identified several mechanisms of the Tat-induced Ca(2+) elevation: 1) lysosomal Ca(2+) mobilization, 2) Ca(2+) release via inositol 1,4,5-trisphosphate-sensitive endoplasmic reticulum pools, and 3) Ca(2+) influx via transient receptor potential vanilloid type 2 (TRPV2) channels. Activation of TRPV2, nonselective cation channels, induced a robust and prolonged neuronal membrane depolarization, thus triggering an additional P/Q-mediated Ca(2+) entry. In vivo microinjection studies indicate a dose-dependent, prolonged bradycardic effect of Tat administration into the nucleus ambiguus of conscious rats, in which neuronal TRPV2 played a major role. Our results support previous studies, indicating that Tat promotes bradycardia and, consequently, may be involved in the QT interval prolongation reported in HIV-infected patients. In the context of an overall HIV-dependent autonomic dysfunction, these Tat-mediated mechanisms may account for the higher prevalence of sudden cardiac death in HIV-1-infected patients compared with general population with similar risk factors. Our results may be particularly relevant in view of the recent findings that significant Tat levels can still be identified in the cerebrospinal fluid of HIV-infected patients with viral load suppression due to efficient antiretroviral therapy.

Chemokine Levels and Chemokine Receptor Expression in the Blood and the Cerebrospinal Fluid of HIV-Infected Patients With Cryptococcal Meningitis and Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome

Human immunodeficiency virus-infected patients with treated cryptococcal meningitis who start combination antiretroviral therapy (cART) are at risk of further neurological deterioration, in part caused by paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We hypothesized that C-IRIS is associated with alterations of chemokine receptor expression on T cells and chemokine concentrations in cerebrospinal fluid (CSF) that enhance recruitment of T-helper 1 cells and/or myeloid cells to the central nervous system. In a prospective study of 128 human immunodeficiency virus-infected patients with cryptococcal meningitis who received antifungal therapy followed by cART, we examined the proportions of CD4(+) and CD8(+) T cells expressing CCR5 and/or CXCR3, in CSF and whole blood and the concentrations of CXCL10, CCL2, and CCL3 in stored CSF and plasma. The proportion of CD4(+) and CD8(+) T cells expressing CXCR3(+)CCR5(+) and the concentrations of CXCL10, CCL2 and CCL3 were increased in CSF compared with blood at cART initiation (P < .0001). Patients with C-IRIS (n = 26), compared with those with no neurological deterioration (n = 63), had higher CSF ratios of CCL2/CXCL10 and CCL3/CXCL10 and higher proportions of CXCR3(+)CCR5(+)CD8(+)T cells in CSF compared with blood at cART initiation (P = .03, .0053, and .02, respectively). CD8(+) T-cell and myeloid cell trafficking to the central nervous system may predispose patients to C-IRIS.

Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy

To determine changes of cerebrospinal fluid (CSF) biomarkers of patients on monotherapy with lopinavir/ritonavir. The Monotherapy Switzerland/Thailand study (MOST) trial compared monotherapy with ritonavir-boosted lopinavir with continued therapy. The trial was prematurely stopped due to virological failure in six patients on monotherapy. It, thus, offers a unique opportunity to assess brain markers in the early stage of HIV virological escape. : Sixty-five CSF samples (34 on continued therapy and 31 on monotherapy) from 49 HIV-positive patients enrolled in MOST. Using enzyme-linked immunosorbent assay, we determined the CSF concentration of S100B (astrocytosis), neopterin (inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-β 1-42 (Aβ), the latter three indicating neuronal damage. Controls were CSF samples of 29 HIV-negative patients with Alzheimer dementia. In the CSF of monotherapy, concentrations of S100B and neopterin were significantly higher than in continued therapy (P = 0.006 and P = 0.013, respectively) and Alzheimer dementia patients (P < 0.0001 and P = 0.0005, respectively). In Alzheimer dementia, concentration of Aβ was lower than in monotherapy (P = 0.005) and continued therapy (P = 0.016) and concentrations of tTau were higher than in monotherapy (P = 0.019) and continued therapy (P = 0.001). There was no difference in pTau among the three groups. After removal of the 16 CSF with detectable viral load in the blood and/or CSF, only S100B remained significantly higher in monotherapy than in the two other groups. Despite full viral load-suppression in blood and CSF, antiretroviral monotherapy with lopinavir/ritonavir can raise CSF levels of S100B, suggesting astrocytic damage.

Critical Role for Antiapoptotic Bcl-xL and Mcl-1 in Human Macrophage Survival and Cellular IAP1/2 (cIAP1/2) in Resistance to HIV-Vpr-induced Apoptosis

Macrophages are resistant to HIV cytopathic effects, which contributes to viral persistence and reservoir formation. HIV viral protein R (Vpr) is a potent apoptosis-inducing agent for primary monocytes. Because the biologically active Vpr is found in serum and cerebrospinal fluid of HIV-infected patients, we investigated the apoptotic effect of Vpr on monocyte-derived macrophages and phorbol 12-myristate 13-acetate-activated THP1 macrophages. Our results show that primary monocytes and THP1 cells develop resistance to Vpr-induced apoptosis following differentiation into macrophages. To determine the effect of Vpr on the expression of antiapoptotic proteins, we show that in contrast to the undifferentiated cells, Vpr did not down-regulate the expression of antiapoptotic inhibitors of apoptosis (IAPs) and Bcl2 family members in macrophages, suggesting their involvement in resistance to Vpr-induced apoptosis. However, knocking down Bcl-xL and Mcl-1 proteins induced spontaneous apoptosis with no impact on susceptibility to Vpr-induced apoptosis. In contrast, down-regulation of cellular IAP1 (cIAP1) and cIAP2 by using siRNAs and SMAC (second mitochondria-derived activator of caspases) mimetic sensitized macrophages to Vpr-induced apoptosis. Overall, our results suggest that resistance to Vpr-induced apoptosis is specifically mediated by cIAP1/2 genes independent of Bcl-xL and Mcl-1, which play a key role in maintaining cell viability. Moreover, IAP modulation may be a potential strategy to eliminate HIV persistence in macrophages.

Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection

To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. To provide the first broad profiles of protein changes in the CSF of HIV-infected patients, we used antibody arrays to measure 120 cytokines, chemokines, growth factors, and other proteins. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV-infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression.

The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons

Background The presence of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid (CSF) is used as a marker of HIV-associated primary central nervous system lymphoma (PCNSL). In our setting, EBV DNA is frequently detected in the CSF of HIV-infected patients with miscellaneous neurological diseases and thus its presence is a poor predictor of PCNSL. Objectives To determine whether quantification of EBV DNA in CSF improves its diagnostic specificity for PCNSL. Study design EBV viral loads were determined on CSF samples from 55 HIV-infected patients with CNS disease. Results Twenty of the 55 patients had detectable EBV DNA in their CSF (median viral load 6120 copies/ml, range 336–1,034,000 copies/ml). PCNSL was confirmed in 2 patients. Their CSF EBV loads were 1,034,000 and 15,460 copies/ml, respectively. Using a cut-off of 10,000 copies/ml improved the specificity and positive predictive value (PPV) compared to a qualitative result for the diagnosis of PCNSL (96% vs. 66% and 50% vs. 10%, respectively). Conclusion EBV DNA is commonly detected in CSF of HIV-infected patients. Quantitative PCR improves the diagnostic specificity, however, the PPV remains too low for it to be used as an isolated marker for PCNSL.

Adenosine deaminase activity in cerebrospinal fluid of HIV-infected patients: limited value for diagnosis of tuberculous meningitis

Adenosine deaminase activity (ADA) determination in cerebrospinal fluid (CSF) is considered a specific test for the diagnosis of tuberculous meningitis. In order to study the variability of this marker in patients with different neurological disorders associated with HIV infection, and its utility for the diagnosis of tuberculous meningitis in these patients, the ADA levels in 417 CSF samples from HIV-infected patients with neurological symptoms were reviewed. HIV infection, HIV-associated neurological disorders, and progressive multifocal leukoencephalopathy were not associated with elevated ADA in CSF. Among patients with meningitis, receiver operating characteristic curve analysis gave an optimal ADA cut-off point of 8.5 IU/l for the diagnosis of tuberculous meningitis, with 57% sensitivity, 87% specificity, and an area under the curve of 0.747 (similar to that for CSF glucose concentration). False-positive results were found in patients with neurological CMV disease and cryptococcal, lymphomatous, and probable candidal meningitis. The results of this study indicate that ADA determination in CSF has limited utility for the diagnosis of tuberculous meningitis in HIV-infected patients.

CMV DNA in blood and CSF of HIV infected patients

Cytomegalovirus (CMV) infection frequently affects the central nervous system in HIV infected patients. Varied clinical manifestations of CMV disease make virological detection of CMV essential for proper diagnosis and treatment. Thus, in patients in different stages of HIV-induced disease, we attempted to detect cell associated and free, non cell associated CMV DNA in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells (PBMCs). Twenty-six blood samples were collected from 22 patients included in the study. Nine of these blood samples were tested in pair with the concomitant CSF sample for the presence of CMV DNA by a commercial hybridization test. CMV serostatus and avidity of IgG antibodies were detected by a commercial ELISA test. CMV DNA was present in the cells found in CSF in all but one of the AIDS patients, independently of the presence of neurological symptoms, suggesting that it represented a marker of advanced immunodeficiency, rather than of the specific CMV-related disease. Cell-associated CMV DNA in CSF tested positive even in the samples negative for cell-free CMV DNA in the CSF, and with no detectable CMV DNA in the PBMCs of concomitant blood sample. We believe that searching for CMV DNA in different compartments of CSF merits further attention.

Increased levels of soluble Fas receptor and Fas ligand in the cerebrospinal fluid of HIV-infected patients.

Analyses of serum samples and blood cells have revealed a dysregulation of the Fas/Fas ligand (FasL) system during HIV infection, which may be related to disease progression. As Fas and FasL have been suggested to participate in brain injury in a variety of CNS disorders, the aim of this study was to determine (1) whether soluble Fas and FasL can be detected in cerebrospinal fluid (CSF) samples from HIV-infected patients, (2) whether levels of these molecules are related to disease progression, and (3) whether levels of sFasL are related to other laboratory findings. Soluble Fas was detected in 38 of 56 (68%) and soluble Fas ligand in 17 of 56 (30%) CSF samples from HIV-infected patients. CSF levels of both molecules correlated neither with the CSF-to-serum albumin ratio nor with corresponding serum concentrations. This finding suggests that they are at least in part produced intrathecally. Levels of both CSF sFas and sFasL correlated significantly and inversely with the blood CD4+ cell counts, suggesting that the intrathecal release of both molecules is increased during progression to advanced immunodeficiency.

Imbalance between IL-1 and IL-1 receptor antagonist in the cerebrospinal fluid of HIV-infected patients.

Inflammatory cytokines (interleukin [IL]-1 and tumor necrosis factor [TNF]) have specific inhibitors (IL-1 receptor antagonist [IL-1Ra] and TNF-soluble receptors), the concentration of which can indicate activation and regulation of this system. We measured IL-1 and IL-1Ra in the cerebrospinal fluid (CSF) of HIV-infected patients and seronegative controls. High IL-1Ra concentrations were found in samples from patients with opportunistic meningoencephalitis, even in the presence of normal cell count and protein content, not in samples from patients with leucoencephalopathies or controls. Therefore, IL-1Ra appears to be a sensitive marker of inflammation in the central nervous system. In contradistinction to previous results obtained from blood measurement, IL-1alpha and IL-1beta remained below detectable levels in all cases, suggesting that IL-1 may be regulated differently in the central nervous system and in the blood.

Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients.

To assess the presence of hepatitis C virus (HCV) in the central nervous system (CNS), HCV-RNA was sought in paired serum and cerebrospinal fluid (CSF) samples of 21 HIV/HCV-positive patients: HCV-RNA was detected in the serum of 19/21 patients (90.4%), and in the CSF of five of the 19 serum-positive patients. The presence of HCV-RNA was confirmed in follow-up CSF samples available for three of these five patients. An identical HCV genotype was found in the paired serum/CSF samples. No correlation was found between the different genotypes and the presence of HCV in CSF of the individual patients. HCV viremia levels measured by branched-DNA and quantitative PCR were not significantly higher in the CSF-positive cases than in the CSF-negative cases (P = 0.3, using b-DNA; 0.5, using quantitative PCR). This report shows the presence of HCV in CSF and raises the possibility that the CNS may act as a reservoir site for HCV.

Varicella-zoster virus (VZV) DNA in cerebrospinal fluid of patients infected with human immunodeficiency virus: VZV disease of the central nervous system or subclinical reactivation of VZV infection?

To identify varicella-zoster virus (VZV) infections of the nervous system in patients infected with human immunodeficiency virus (HIV), polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) samples from 514 consecutive HIV-infected patients with neurological disease was performed to detect VZV DNA. VZV DNA was detected in CSF of 13 (2.5%) of 514 patients. Four of 13 patients had VZV encephalitis or meningoencephalomyelitis. These four patients received intravenous acyclovir therapy; CSF became negative for VZV DNA and clinical conditions improved for two, whereas CSF remained positive for VZV DNA and clinical conditions worsened until death for two. In nine of 13 patients, the neurological symptoms were likely caused by other simultaneous HIV-related complications in the central nervous system. After intravenous therapy with high doses of acyclovir or foscarnet, VZV was cleared from CSF in eight of nine patients. VZV DNA can be detected in CSF of HIV-infected patients in association with either manifestations of neurological VZV disease or subclinical reactivation of VZV infection. Antiviral treatment may be effective in suppressing VZV replication in the nervous system.