T3 level may be a helpful marker to predict disease prognosis of acute central nervous system viral infections.

AIM OF THE STUDY: Acute central nervous system viral infections are progressive and inflammatory diseases with inflammatory cells infiltrating into the central nervous system (CNS), and thyroid hormone (TH) level is associated with the oxidative and antioxidant status. Variations in oxidative stress and antioxidant status are related to the pathogenesis of inflammatory diseases. Our study aimed to investigate the possible correlation between viral infections in CNS and TH levels of thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3). MATERIALS AND METHODS: We measured serum concentrations of TSH, fT4, and fT3 in 206 individuals, including 59 viral meningitis (VM) patients, 60 viral encephalitis (VE) patients, and 87 healthy controls. RESULTS: Our findings showed that VE and VM patients had lower levels of fT3 and higher levels of fT4 compared with healthy controls, whether male or female. Moreover, levels of TSH and fT3 in patients with viral infections in CNS were inversely correlated with disease prognosis measured by the Glasgow Outcome Scale. CONCLUSIONS: Variations in TH level may represent the oxidative status and are surrogate biomarkers for disease prognosis of acute central nervous system viral infections.

Accuracy of Herpes Simplex Virus Polymerase Chain Reaction Testing of the Blood for Central Nervous System Herpes Simplex Virus Infections in Infants.

There were 1038 infants with herpes simplex virus polymerase chain reaction testing performed of blood and cerebrospinal fluid specimens. There were 21 (2.0%) with a positive cerebrospinal fluid PCR, of whom 16 also had a positive blood PCR (sensitivity 76%; 95% CI, 53%-92%). Blood PCR cannot exclude herpes simplex virus central nervous system infection.

Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: To evaluate the diagnostic and prognostic utility of monitoring the Epstein-Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV-associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 172 patients undergoing allo-HSCT were enrolled in the study. METHODS: The EBV DNA levels of blood were monitored regularly in recipients of transplants for 3 years post transplantation. The EBV DNA levels of CSF were monitored in patients with EBV-associated CNS diseases before the treatment and at different points following the treatment. RESULTS: Post-transplant EBV-associated diseases developed in 27 patients, including 12 patients with EBV-associated CNS diseases. The 3-year cumulative incidences of EBV-associated diseases and EBV-associated CNS diseases were 19.5 ± 3.5% and 8.6 ± 2.4%, respectively. Patients with EBV-associated diseases showed higher loads of EBV DNA in their blood compared with patients with EBV DNA-emia. No difference was seen between the EBV DNA levels of blood in patients with CNS involvement and patients without CNS involvement. The EBV DNA loads of blood increased 3-14 days before the clinical manifestations of EBV-associated diseases emerged. The EBV DNA loads of CSF were higher than that of blood in patients with EBV-associated CNS diseases. In 12 patients with EBV-associated CNS diseases, EBV DNA levels were declining in both blood and CSF with the control of diseases, and the EBV DNA loads of CSF decreased faster than that of blood in 5 patients who responded to treatment, and the EBV DNA levels of CSF increased in 5 patients who were unresponsive to treatment. On multivariate analysis, the use of anti-thymocyte globulin and intensified conditioning regimens were independent risk factors for EBV-associated diseases and EBV-associated CNS diseases. CONCLUSIONS: EBV-associated CNS diseases are not rare after allo-HSCT. The EBV DNA loads of CSF could act as an important indicator, but the EBV DNA loads of blood could not, for the diagnosis, prognosis, and therapeutic evaluation of EBV-associated CNS diseases.

Lack of cerebrospinal fluid pleocytosis in young infants with enterovirus infections of the central nervous system.

OBJECTIVES: To identify factors associated with cerebrospinal fluid (CSF) pleocytosis among infants aged 90 days or younger with enterovirus (EV) infections of the central nervous system (CNS). METHODS: This is a retrospective cohort study performed at an urban academic children's hospital. Patients aged 90 days or younger with a positive CSF EV polymerase chain reaction (PCR) test result obtained during the EV seasons from 2000 to 2006 were included. Patients with concomitant serious bacterial illness or herpes simplex virus infection were excluded. Multivariable logistic regression was used to identify factors independently associated with CSF pleocytosis. RESULTS: A total of 159 patients had a positive CSF EV PCR test result during the study period; 5 (3.1%) were excluded for concurrent serious bacterial infection. The median CSF white blood cell (WBC) count was 110/microL (interquartile range, 11-311/microL). Cerebrospinal fluid pleocytosis was present in 109 patients (71%). The proportion of infants with CSF pleocytosis accompanying EV CNS infections increased with age; CSF pleocytosis was present in 59%, 74%, and 90% of infants aged 0 to 28, 29 to 56, and 57 to 90 days, respectively (P = 0.007). Age and peripheral WBC count were independently associated with CSF pleocytosis. CONCLUSIONS: Among infants with EV CNS infections, the absence of CSF pleocytosis is related to younger age and lower peripheral WBC counts, perhaps reflecting the decreased ability of younger infants to mount a robust inflammatory response to EV infection. Thus, CSF EV PCR testing may be warranted in select patients without CSF pleocytosis.

Cytokine biomarkers associated with clinical cases of acute flaccid myelitis.

Acute flaccid myelitis (AFM) is a serious neurological illness first recognized in the United States in 2014, with subsequent outbreaks every two years. Following extensive etiologic testing by multiple laboratories of hundreds of specimens collected from patients diagnosed with AFM, no consistent cause of AFM has been identified. However, viruses, including enteroviruses, have been implicated through detection in non-sterile site specimens and antibody studies. Cytokines and chemokines play important roles in the modulation of the innate and adaptive immune response to pathogens. In the current study, we measured levels of cytokines and chemokines in serum and CSF collected from confirmed AFM patients and non-AFM control patients, to identify unique biomarkers as potential hallmarks of AFM pathogenesis. Analysis of ratios of cytokines and chemokines in the CSF compared to the serum indicate that the pro-inflammatory cytokines/chemokines IP-10 and IL-6 were significantly elevated in AFM patients compared to non-AFM patients. These results may provide additional insight into potential etiologies, pathogenic mechanisms, and treatments for AFM.

Contribution of Enteroviruses to Acute Central Nervous System or Systemic Infections in Northern Italy (2015-2017): Is It Time to Establish a National Laboratory-Based Surveillance System?

BACKGROUND: Enteroviruses (EVs) can cause infections and outbreaks of mild to severe diseases, such as central nervous system (CNS) and systemic infections. The contribution of EVs to acute CNS/systemic infections requiring hospitalization was assessed by analysing data extracted from virology laboratory database. METHODS: Real-life data obtained from two molecular virology laboratories located in Northern Italy were retrieved from databases and analysed retrospectively. The queries used to extract the data were (i) requests for EV-RNA detection in clear cerebrospinal fluid (CSF) specimens collected from hospitalized patients with suspected acute CNS (including aseptic meningitis, encephalitis, and acute flaccid myelitis/paralysis) or systemic infections (sepsis-like illness or fever (≥ 38°C) of unknown origin), (ii) CSF samples collected from January 1st, 2015, to December 31st, 2017. RESULTS: 582 requests of EV-RNA detection in CSF samples collected from as many patients of any age were recorded. EV-RNA was detected in 4.5% of the CSF samples; 92.3% of EV-positive cases were patients < 15 years, 58.3% of whom were < 3 months. EVs circulated all-year-round, and the highest EV-positive rates were observed from May to August. The risk of EV infection and the relative illness ratio value among children < 1 - year - old were significantly higher than those observed for older patients. CONCLUSIONS: EV surveillance should be carried out for all pediatric patients < 15 years and especially children less than 1 year of age with clinically suspected CNS infection/systemic infections. The implementation of a laboratory-based surveillance established for analysing the virological data provided by laboratories that routinely perform EV molecular testing may enable us to determine the impact of EVs that can cause infections requiring hospitalization.

Chikungunya virus and central nervous system infections in children, India.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus best known for causing fever, rash, arthralgia, and occasional neurologic disease. By using real-time reverse transcription-PCR, we detected CHIKV in plasma samples of 8 (14%) of 58 children with suspected central nervous system infection in Bellary, India. CHIKV was also detected in the cerebrospinal fluid of 3 children.

Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.

Acute flaccid myelitis (AFM) has caused motor paralysis in >560 children in the United States since 2014. The temporal association of enterovirus (EV) outbreaks with increases in AFM cases and reports of fever, respiratory, or gastrointestinal illness prior to AFM in >90% of cases suggest a role for infectious agents. Cerebrospinal fluid (CSF) from 14 AFM and 5 non-AFM patients with central nervous system (CNS) diseases in 2018 were investigated by viral-capture high-throughput sequencing (VirCapSeq-VERT system). These CSF and serum samples, as well as multiple controls, were tested for antibodies to human EVs using peptide microarrays. EV RNA was confirmed in CSF from only 1 adult AFM case and 1 non-AFM case. In contrast, antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%), significantly higher than controls, including non-AFM patients (1/5 [20%]), children with Kawasaki disease (0/10), and adults with non-AFM CNS diseases (2/11 [18%]) (P = 0.023, 0.0001, and 0.0028, respectively). Six of 14 CSF samples (43%) and 8 of 11 sera (73%) from AFM patients were immunoreactive to an EV-D68-specific peptide, whereas the three control groups were not immunoreactive in either CSF (0/5, 0/10, and 0/11; P = 0.008, 0.0003, and 0.035, respectively) or sera (0/2, 0/8, and 0/5; P = 0.139, 0.002, and 0.009, respectively).IMPORTANCE The presence in cerebrospinal fluid of antibodies to EV peptides at higher levels than non-AFM controls supports the plausibility of a link between EV infection and AFM that warrants further investigation and has the potential to lead to strategies for diagnosis and prevention of disease.

[Central nervous system viral infections--analysis of routine laboratory results]. / Diagnostyka wirusowych zakazen osrodkowego ukladu nerwowego--analiza wyników rutynowych badan laboratoryjnych.

The most of registered in Poland cases of encephalitis and meningitis have viral aetiology. Confirmation of viral central nervous system (CNS) infection and diagnosis of pathogenic agent is critical for therapeutic treatment, especially if antiviral chemotherapy is available. The aim of this work was analysis of routine laboratory results obtained in Laboratory of Department of Virology NIZP-PZH by examination of materials obtained from 82 medical canters in Poland in aim of CNS infection confirmation. Materials, cerebrospinal fluid (CSN) n=277, and CSN together with serum (n=452) were obtained from patients aged from 3 days to 83 years. Accordingly with the range of tests performed in Laboratory of Department of Virology NIZP-PZH, obtained samples were examinated for 11 viral infections: HSV, CMV, EBV, VZV, HHV-6, HHV-7, TBE, measles, mumps, rubella and enteroviruses. Confirmation of viral infection was obtained in 104 out of 729 tested patients (14.3%). The highest number of confirmations was obtained in case of TBE infection (18.4%) and HSV (9.2%). The methods gave the highest number of confirmations were testing of intrathecal IgG synthesis (14.4%) and presence of IgM in serum (10.3%). If test was conducted only with CSF, confirmation of viral infection was obtained in 13 cases (4.7%). In conclusions it was ascertained that testing CSF and serum samples together greatly increase possibility of etiological agent detection and a range of ordered tests (i.e. intrathecal synthesis versus PCR) should account dynamics of pathological process.

Low serum uric acid levels in patients with acute central nervous system viral infections.

Most acute central nervous system (CNS) viral infections lead to either encephalitis or meningitis. Many neurotropic viruses may cause CNS dysfunctions through various mechanisms including oxidative stress. Serum uric acid (SUA) levels, which are associated with oxidative stress and antioxidant status, are reduced in patients with various neurological disorders, including multiple sclerosis. We investigated the possible correlation between SUA levels and clinical disease status in patients with acute CNS viral infections. We measured SUA concentrations in 336 individuals, including 179 healthy individuals and 157 patients with acute CNS viral infections. We found that the patients had lower SUA levels than the healthy individuals did irrespective of sex. Effective therapy significantly increased SUA levels. The patients' SUA levels were correlated inversely with outcomes as measured with the Glasgow Outcome Scale. SUA levels may be a biomarker for predicting treatment outcomes and prognoses for patients with acute CNS viral infections with inflammatory components.

Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study.

BACKGROUND: Cerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings. METHODS: To explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined. FINDINGS: Plasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4(+) T cells. INTERPRETATION: These results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

HIV-1 RNA levels in cerebrospinal fluid and plasma and their correlation with opportunistic neurological diseases in a Brazilian AIDS reference hospital.

BACKGROUND: Plasma HIV RNA levels reflect systemic viral replication but in CNS it may occur relatively independent of systemic infection, yet clinical application of CSF HIV-1 RNA levels is less clear. OBJECTIVE: To compare CSF and plasma HIV-1 RNA levels of patients with different opportunistic neurological diseases to those without neurological disease, as well as to correlate these levels with the outcome of the disease and use of HAART. METHOD: 97 patients who had lumbar puncture for routine work up of suspected neurological diseases, were divided in 2 groups: without neurological disease (23) and with neurological disease (74). NASBA was used for plasma and CSF HIV RNA. RESULTS: Median CSF viral load was higher in toxoplasmic encephalitis, cryptococcal meningitis, HIV dementia and neurological diseases without a defined etiology when compared to patients without neurological disease. There was no difference between plasma viral load in patients with and without neurological diseases. Median viral load was higher in plasma and CSF among patients who died when compared to those successfully treated. CSF and plasma viral load were lower in patients with opportunistic diseases on HAART than without HAART. CONCLUSION: CSF viral load was higher in patients with any neurological disease, but this difference was not present in plasma viral load, suggesting that neurological disease influences more the CSF than plasma compartments. Notwithstanding different neurological diseases were not possible to be differentiated by the levels of CSF HIV-1.

Herpes Consensus PCR test: a useful diagnostic approach to the screening of viral diseases of the central nervous system.

BACKGROUND: Infections of the central nervous system (CNS) are a difficult diagnostic problem for both clinicians and microbiologists. Various clinical signs, such as encephalitis, myelitis, meningitis, may be associated with herpesviruses. The use of multiplex 'Herpes Consensus' polymerase chain reaction (HC-PCR) in association with nested PCR (nPCR), in addition to classical techniques, made it possible to optimise the management of cerebrospinal fluid (CSF) and serum samples from patients affected by these viral diseases of the CNS. OBJECTIVES: To test by HC-PCR by nPCR and cell culture the CSF and sera from patients with viral infections of the CNS. STUDY DESIGN: We analysed 320 CFS, 154 serum samples and 11 various samples from 286 patients with clinically suspected encephalitis, meningitis or other diseases of the CNS by HC-PCR, nPCR and traditional investigations (cell culture and serological tests). RESULTS: On molecular analysis with the HC-PCR test, 51 CFS samples (15.9%) were positive for at least one of the six target Herpes viruses: fourteen for Herpes simplex 1 (HSV-1), seven for HSV-2, 12 for Cytomegalovirus (CMV; one of which was from an HIV-positive patient), five for Epstein-Barr virus (EBV; four of which were from HIV-positive patients), three for Varicella-Zoster virus (VZV), five for Human Herpes virus type 6 (HHV-6), three for HSV-1 with HHV-6 co-infection (two cases) and HSV-2 co-infection (one case), and two for HHV-6 with CMV or EBV co-infection (both from patients with immune deficiency). A further 12 samples were positive in nPCR for HHV-7 (8), ADV (1), Enterovirus (1), HSV-1 (1), EBV (1). Of the 154 serum samples, 17 (11.0%) tested positive by HC-PCR for HSV-1 (4), HSV-2 (1), CMV(1), EBV(1), VZV(3) or HHV-6(6), 1 with co-HSV-2/VZV infection. A further five samples tested positive for HHV-7 in nPCR. Culture and tests for antibodies did not supply sufficiently sensitive and specific data. CONCLUSIONS: Our laboratory experience shows that herpesviruses play a central aetiological role in viral infections of the CNS. PCR analysis, especially the HC-PCR test, have revolutionised the diagnostic approach to such infections, making possible rapid, specific and highly sensitive baseline screening. In this way, microbiological investigations can lead to prompt diagnosis, which was limited in the past to a very small number of cases.

Laboratory diagnosis of central nervous system infections caused by herpesviruses.

BACKGROUND: Herpesviruses may be associated with various types of central nervous system (CNS) infections. Herpes simplex encephalitis (HSE) has to be considered one of the most severe diseases. As effective antiviral drugs are available, rapid and reliable diagnosis has become important. OBJECTIVES: To describe polymerase chain reaction (PCR) and serological methods for the detection of herpesvirus-induced CNS infections by the example of HSE. STUDY DESIGN: 620 cerebrospinal fluid (CSF) and 2400 serum samples from 2700 selected hospitalized patients with clinical suspicion of encephalitis were tested for herpes simplex virus (HSV) as well as varicella-zoster virus (VZV) DNA and HSV-specific antibodies, respectively. RESULTS: HSV-1 DNA could be detected in eight and HSV-2 in three patients with focal encephalitis. In addition, HSV-2 DNA was found in two newborns with encephalitis and two adults suffered from transverse lumbar myelitis. One VZV DNA-positive patient had developed herpes zoster accompanied by meningoencephalitis, and in the other an encephalitis without cutaneous rash was diagnosed. Intrathecal antibody synthesis could be measured when CSF was cleared from viral DNA. CONCLUSIONS: The detection of viral DNA by PCR technique has become the "gold standard" method for laboratory diagnosis of herpesvirus infections of CNS. Serodiagnosis may be useful to confirm the diagnosis retrospectively.

Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers.

OBJECTIVE: Elite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20-50 copies/ml) in the absence of antiretroviral therapy. Here, we examine to what extent elite controllers also control infection of the central nervous system (CNS). DESIGN: We analysed paired cerebrospinal fluid (CSF) and plasma samples using a highly sensitive assay for HIV-1 RNA quantification. METHODS: We analysed 28 CSF samples and 27 concurrent plasma samples from 14 elite controllers with the highly sensitive single-copy assay (SCA) that allows for HIV-1 RNA quantification down to less than one copy of HIV-1 RNA per millilitre. RESULTS: Three samples were excluded because of internal standard failure. HIV-1 RNA was detected in only five of 26 CSF samples compared with 14 of 26 plasma samples (P = 0.02), with a median of 0.2 (range, 0.1-6) copies/ml in CSF compared with 0.8 (range, 0.1-189 copies/ml) in plasma (P < 0.0001). CONCLUSION: HIV-1 RNA could not be detected in CSF in most elite controllers using the highly sensitive SCA, and when detected, it was at significantly lower frequencies and concentrations than in plasma. Elite controllers thus control HIV-1 in the CNS very well. Whether the infrequent and small amounts of HIV-1 RNA in the CSF reflect production from a local reservoir or virion exchange between the blood and the CSF is uncertain.

Analysis of correlation between cerebrospinal fluid and plasma HIV-1 RNA levels in patients with neurological opportunistic diseases.

The question of whether HIV-1 RNA in cerebrospinal fluid (CSF) is derived from viral replication in the central nervous system or simply reflects the transit of infected lymphocytes from the blood compartment has long been a matter of debate. Some studies found no correlation between CSF and plasma viral load, whereas others did. The lack of a correlation between the two compartments suggests that the presence of HIV-1 RNA is not simply due to the passive passage of the virus from blood to CSF but rather due to intrathecal replication. To evaluate the correlation between plasma and CSF HIV-1 RNA levels and to identify situations in which there is no correlation between the two compartments, seventy patients were prospectively studied. The association between CSF and plasma viral load was evaluated in the total population and in subgroups of patients with similar characteristics. A correlation between the CSF and plasma compartments was observed for patients undergoing highly active antiretroviral therapy (HAART), those with a CD4 T lymphocyte count lower than 200 cells/mm³, and those with increased CSF protein content. On the other hand, no correlation was observed for patients without adequate virological control, who had a CD4 count higher than 200 cells/mm³ and who did not use HAART. The correlation between the two compartments observed in some patients suggests that CSF HIV-1 RNA levels may reflect plasma levels in these subjects. In contrast, the lack of a correlation between the two compartments in patients who were not on HAART and who had normal CSF proteins and a poor virological control possibly indicates compartmentalization of the virus in CSF and, consequently, plasma-independent intrathecal viral replication.

A serological analysis of viral and bacterial infections associated with neuromyelitis optica.

To evaluate the role of infections in the development of neuromyelitis optica (NMO), 19 patients positive for anti-aquaporin-4 antibody were screened for 24 viral and bacterial infections. Serological evidence of recent viral infection was found in 7 of 15 patients screened during the acute phase of the neurologic illness, which was a significantly more frequent rate of infection than seen in the control group of 33 patients with neurodegenerative, metabolic, or vertebral diseases (47% versus 15%). Mumps virus and human herpes viruses were the frequent causal agents, although there was no statistical difference in frequency between the two groups. Most patients with identified recent infection had monophasic or recurrent myelitis without evidence of optic nerve involvement and small number of total clinical relapses. Disease history tended to be shorter in patients with identified recent infection than those without, and an expanded long spinal cord lesion in magnetic resonance imaging was rarely found in patients with identified recent infection, although statistical significance could not be shown. These findings indicate that, not single, but various viral infections, can be associated with the development of NMO during the early stages of the illness, although the exact pathogenesis of NMO has yet to be clarified.

A plasma microRNA signature of acute lentiviral infection: biomarkers of central nervous system disease.

OBJECTIVE: Plasma microRNAs (miRNAs) are modulated during disease and are emerging biomarkers; they have not been characterized in HIV infection. Using our macaque/simian immunodeficiency virus (SIV) model of HIV, we sought to identify a plasma miRNA profile of acute lentiviral infection, evaluate its relationship with known cellular and viral determinants of lentivirus-associated central nervous system (CNS) disease, and explore the potential of miRNAs to predict CNS disease. DESIGN: Plasma samples were obtained before inoculation and 10 days after inoculation from SIV-infected macaques. METHODS: Plasma miRNA expression profiles were determined by TaqMan low-density array for six individuals. miRNA expression was compared with levels of cytokines, virus, and plasma platelet count. miRNA results were confirmed by single miRNA-specific assays for 10 macaques. Nineteen individuals were used to validate a disease prediction test. RESULTS: A 45-miRNA signature of acute infection (differential expression with P < 0.05 after multiple comparison correction) classified plasma as infected or not. Several differentially expressed miRNAs correlated with CNS disease-associated cytokines interleukin-6 and CCL2 and included predicted and/or validated regulators of the corresponding mRNAs. miRNAs tracked with viral load and platelet count were also predictors of CNS disease. At least six miRNAs were significantly differentially expressed in individuals with severe versus no CNS disease; in an unweighted expression test, they predicted CNS disease. CONCLUSION: Acute-phase differential expression of plasma miRNAs predicts CNS disease and suggests that CNS damage or predisposition to disease progression begins in the earliest phase of infection. Plasma miRNAs should be investigated further as leading indicators of HIV diseases as early as acute infection.

Analysis of correlation between cerebrospinal fluid and plasma HIV-1 RNA levels in patients with neurological opportunistic diseases / Análise da correlação entre os níveis de RNA do HIV-1 no líquido cefalorraquidiano e plasma em pacientes com doença neurológica oportunista

The question of whether HIV-1 RNA in cerebrospinal fluid (CSF) is derived from viral replication in the central nervous system or simply reflects the transit of infected lymphocytes from the blood compartment has long been a matter of debate. Some studies found no correlation between CSF and plasma viral load, whereas others did. The lack of a correlation between the two compartments suggests that the presence of HIV-1 RNA is not simply due to the passive passage of the virus from blood to CSF but rather due to intrathecal replication. To evaluate the correlation between plasma and CSF HIV-1 RNA levels and to identify situations in which there is no correlation between the two compartments, seventy patients were prospectively studied. The association between CSF and plasma viral load was evaluated in the total population and in subgroups of patients with similar characteristics. A correlation between the CSF and plasma compartments was observed for patients undergoing highly active antiretroviral therapy (HAART), those with a CD4 T lymphocyte count lower than 200 cells/mm³, and those with increased CSF protein content. On the other hand, no correlation was observed for patients without adequate virological control, who had a CD4 count higher than 200 cells/mm³ and who did not use HAART. The correlation between the two compartments observed in some patients suggests that CSF HIV-1 RNA levels may reflect plasma levels in these subjects. In contrast, the lack of a correlation between the two compartments in patients who were not on HAART and who had normal CSF proteins and a poor virological control possibly indicates compartmentalization of the virus in CSF and, consequently, plasma-independent intrathecal viral replication.

Tem sido objeto de debate a questão se o RNA do HIV-1 no líquido cefalorraquidiano (LCR) é derivado da replicação viral no sistema nervoso central ou simplesmente reflete o tráfego de linfócitos infectados do compartimento sanguíneo. Alguns estudos não mostraram correlação entre a carga viral do plasma e LCR, mas outros sim. A falta de correlação entre os dois compartimentos sugere que a presença de RNA do HIV-1 não é simplesmente devido à passagem do vírus do plasma para o LCR, mas sim a uma replicação intratecal. Para avaliar a correlação entre os níveis de RNA do HIV-1 no plasma e no LCR e tentar identificar situações, na qual, não existe a correlação entre os dois compartimentos avaliaram-se setenta pacientes prospectivamente. A associação entre a carga viral do LCR e plasma foi avaliada na população total e em subgrupos de pacientes com características similares. A correlação entre os dois compartimentos foi observada em pacientes que estavam em uso da terapia antiretroviral (HAART), naqueles que tinham contagem de linfócitos CD4 menor que 200 céls/mm³ e naqueles com aumento da concentração de proteínas no LCR. Por outro lado, não houve correlação para os pacientes que não tinham um controle virológico adequado, os que tinham contagem de CD4 maior que 200 céls/mm³ e aqueles que não estavam usando HAART. A correlação entre os dois compartimentos observada em alguns pacientes sugere que os níveis de RNA do HIV-1 no LCR podem refletir os níveis plasmáticos nestes pacientes. E a falta de correlação ente os dois compartimentos em pacientes que não usavam HAART, nos que tinham uma concentração de proteínas no LCR normal, e nos que não apresentavam bom controle virológico, indica provavelmente a compartimentalização do vírus no LCR e consequentemente replicação viral intratecal independente da do plasma.

High pathogenicity of wild-type measles virus infection in CD150 (SLAM) transgenic mice.

Measles virus (MV) infection causes an acute childhood disease, associated in certain cases with infection of the central nervous system and development of a severe neurological disease. We have generated transgenic mice ubiquitously expressing the human protein SLAM (signaling lymphocytic activation molecule), or CD150, recently identified as an MV receptor. In contrast to all other MV receptor transgenic models described so far, in these mice infection with wild-type MV strains is highly pathogenic. Intranasal infection of SLAM transgenic suckling mice leads to MV spread to different organs and the development of an acute neurological syndrome, characterized by lethargy, seizures, ataxia, weight loss, and death within 3 weeks. In addition, in this model, vaccine and wild-type MV strains can be distinguished by virulence. Furthermore, intracranial MV infection of adult transgenic mice generates a subclinical infection associated with a high titer of MV-specific antibodies in the serum. Finally, to analyze new antimeasles therapeutic approaches, we created a recombinant soluble form of SLAM and demonstrated its important antiviral activity both in vitro and in vivo. Taken together, our results show the high susceptibility of SLAM transgenic mice to MV-induced neurological disease and open new perspectives for the analysis of the implication of SLAM in the neuropathogenicity of other morbilliviruses, which also use this molecule as a receptor. Moreover, this transgenic model, in allowing a simple readout of the efficacy of an antiviral treatment, provides unique experimental means to test novel anti-MV preventive and therapeutic strategies.