Cerebrospinal fluid viral escape in HIV patients on antiretroviral therapy: A systematic review of reported cases.

Cerebrospinal fluid (CSF) viral escape rarely occurs when HIV is detected in the CSF, while it is undetectable in the blood plasma or detectable in CSF at levels that exceed those in the blood plasma. We conducted this review to comprehensively synthesise its clinical presentation, diagnosis, management strategies and treatment outcomes. A review registered with PROSPERO (CRD42023475311) searched evidence across PubMed/MEDLINE, Embase, Web of Science, Scopus, and Google Scholar to gather articles (case reports/series) that report on CSF viral escape in people living with HIV (PLHIV) on antiretroviral therapy (ART). The quality of studies was assessed based on the domains of selection, ascertainment, causality, and reporting. A systematic search identified 493 articles and 27 studies that include 21 case reports, and six case series were involved in the review. The studies reported 62 cases of CSF viral escape in PLHIV. The majority were men (66.67%), with a median age of 43 (range: 28-73) years. Approximately, 31 distinct symptoms were documented, mostly being cognitive dysfunction, gait abnormalities, and tremors (12.51%). Diagnosis involved blood and CSF analysis, magnetic resonance imaging, and neuropsychological assessments. Over 36 ART regimens were employed, with a focus on ART intensification; almost one-third of the regimens contained Raltegravir (integrase strand transfer inhibitor). The outcomes showed 64.49% full recovery, 30.16% partial recovery, and 4.76% died. When neuropsychological symptoms manifest in PLHIV, monitoring for CSF viral escape is essential, regardless of plasma viral suppression. Personalised treatment strategies, particularly ART intensification, are strongly advised for optimising treatment outcomes in PLHIV diagnosed with CSF HIV escape.

Microbiomes detected by cerebrospinal fluid metagenomic next-generation sequencing among patients with and without HIV with suspected central nervous system infection.

BACKGROUND: Opportunistic infections in the central nervous system (CNS) can be a serious threat to people living with HIV. Early aetiological diagnosis and targeted treatment are crucial but difficult. Metagenomic next-generation sequencing (mNGS) has significant advantages over traditional detection methods. However, differences in the cerebrospinal fluid (CSF) microbiome profiles of patients living with and without HIV with suspected CNS infections using mNGS and conventional testing methods have not yet been adequately evaluated. METHODS: We conducted a retrospective cohort study in the first hospital of Changsha between January 2019 and June 2022 to investigate the microbiomes detected using mNGS of the CSF of patients living with and without HIV with suspected CNS infections. The pathogens causing CNS infections were concurrently identified using both mNGS and traditional detection methods. The spectrum of pathogens identified was compared between the two groups. RESULTS: Overall, 173 patients (140 with and 33 without HIV) with suspected CNS infection were enrolled in our study. In total, 106 (75.7%) patients with and 16 (48.5%) patients without HIV tested positive with mNGS (p = 0.002). Among the enrolled patients, 71 (50.7%) with HIV and five (15.2%) without HIV tested positive for two or more pathogens (p < 0.001). Patients with HIV had significantly higher proportions of fungus (20.7% vs. 3.0%, p = 0.016) and DNA virus (59.3% vs. 21.2%, p < 0.001) than those without HIV. Epstein-Barr virus (33.6%) was the most commonly identified potential pathogen in the CSF of patients living with HIV using mNGS, followed by cytomegalovirus (20.7%) and torque teno virus (13.8%). The top three causative pathogens identified in patients without HIV were Streptococcus (18.2%), Epstein-Barr virus (12.1%), and Mycobacterium tuberculosis (9.1%). In total, 113 patients living with HIV were diagnosed as having CNS infections. The rate of pathogen detection in people living with HIV with a CNS infection was significantly higher with mNGS than with conventional methods (93.8% vs. 15.0%, p < 0.001). CONCLUSION: CSF microbiome profiles differ between patients living with and without HIV with suspected CNS infection. mNGS is a powerful tool for the diagnosis of CNS infection among people living with HIV, especially in those with mixed infections.

Cerebrospinal Fluid Biomarkers of Symptomatic Neurosyphilis in People With HIV Compared with Uninfected Individuals.

We evaluated the diagnostic clinical performance characteristics (DCPC) of cerebrospinal fluid (CSF) total protein (TP), white blood cell count (WBC), and lactate (LA) with different cutoff points as adjunct biomarkers of confirmed or presumptive symptomatic neurosyphilis (NS) and the impact of HIV infection. From 5,640 participants who underwent lumbar punctures, 236 participants were included, and classified as either people with HIV (PWH) or people without HIV (PWoH) according to the CDC criteria for confirmed NS (n = 42), presumptive NS (n = 74), systemic syphilis (SS) (n = 38), serological diagnosis of syphilis (n = 18), PWH without SS and NS (n = 10), and negative control (n = 72). In PWoH, for presumptive NS, the combination of CSF TP > 45 mg/dL and/or WBC > 5.0 cells/mm3 is valuable for screening, whereas in PWH, it is not recommended for either screening or case-finding NS, however the DCPC were better in the suppressed group. In PWoH, the value of CSF TP > 45 mg/dL is adequate for both screening and confirmation of presumptive NS, subject to prevalence. For WBC count > 20 cell/mm3, the positive predictive value (PPV) of the test is almost perfect, suggesting a confirmatory test. In PWH, CSF TP is an inadequate marker of NS. The WBC count, with cutoffs of > 10 or > 20 cells/mm3, was moderately applicable for screening.As conclusions: CSF WBC count and TP showed distinct DCPC in confirmed or presumptive NS, better in the former. These biomarkers could be included for presumptive NS diagnosis. DCPC of these biomarkers for the diagnosis of NS is greatly affected by HIV co-infection.

Severe CSF immune cell alterations in cryptococcal meningitis gradually resolve during antifungal therapy.

Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy.

IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis.

OBJECTIVES: To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS). METHODS: Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients. RESULTS: Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients. CONCLUSIONS: HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis.

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.

Seropositivity and reactivations of HSV-1, but not of HSV-2 nor VZV, associate with altered blood-brain barrier, beta amyloid, and tau proteins in people living with HIV.

Among 128 adult people living with HIV and no neurological conditions confounding the cerebrospinal fluid results, the presence of HSV-1 chronic infection (detected either by serology or PCR), but not of HSV-2 and VZV, independently associated with higher odds of blood-brain barrier impairment, abnormally increased cerebrospinal fluid levels of tau and phosphorylated-181 tau, and decreased concentrations of fragments 1-42 of beta amyloid compared to the seronegative counterpart. These associations were even stronger for seropositive participants with a positive history of at least one symptomatic reactivation of HSV-1.

Correlations between cerebrospinal fluid biomarkers, neurocognitive tests, and resting-state electroencephalography (rsEEG) in patients with HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in people living with HIV (PLWH) despite successful treatment with combination antiretroviral therapy (cART). HAND pathogenesis is complex and definitive surrogate biomarkers are not clearly defined. Brain function has been assessed through the evaluation of cortical source rhythms with delta waves associated with neurological impairment. The aim of this study was to assess the correlation between EEG cortical sources, cerebrospinal fluid (CSF) biomarkers, and neurocognitive tests in PLWH with HAND. PLWH with HAND without significant comorbidities were enrolled. Baseline rsEEG-LORETA waves, CSF biomarkers (t-tau, p-tau, ß-amiloid42, neopterin, S100ß), and neurocognitive tests were correlated and compared through non-parametric tests (Spearman's rho and Mann-Whitney); data are presented as medians (interquartile ranges). Fifty-four patients were enrolled. Median time of suppressed HIV-RNA and CD4+ T-lymphocyte were 10 years (5.5-15) and 691/uL (477-929). Thirty-nine participants (72%) underwent CSF collection: abnormal biomarkers were found in a small percentage. Only neopterin showed a statistically significant correlation with delta activity [parietal (rho 0.579; p < 0.001), occipital (rho 0.493; p = 0.007), and global sources (rho 0.464 p = 0.011)]. Seven patients (12.9%) showed an abnormal neopterin level (> 1.5 ng/mL) with significantly higher delta source activity compared to the ones with in-range concentrations. We observed a statistically significant correlation between working memory test Trail Making B with both CSF neopterin levels and delta waves (p values < 0.05). In a small sample of PLWH with HAND, we observed that higher CSF neopterin levels were associated with higher EEG delta waves and worse working memory tests.

HIV Compartmentalization in the CNS and Its Impact in Treatment Outcomes and Cure Strategies.

PURPOSE OF REVIEW: This review focuses on the cerebrospinal fluid (CSF) findings in connection to the central nervous system (CNS) reservoir in treatment-naïve and virally suppressed PLWH, followed by the findings in CSF HIV-1 escape and analytical treatment interruption studies. RECENT FINDINGS: Compared to chronic infection, initiating antiretroviral therapy (ART) during acute HIV-1 infection results in more homogeneous longitudinal benefits in the CNS. Viral variants in CSF HIV-1 escape are independently linked to infected cells from the systemic reservoir and in the CNS, highlighting the phenomenon as a consequence of different mechanisms. HIV-infected cells persist in CSF in nearly half of the individuals on stable ART and are associated with worse neurocognitive performance. Future studies should probe into the origin of the HIV-infected cells in the CSF. Examining the capacity for viral replication would provide new insight into the CNS reservoir and identify strategies to eradicate it or compensate for the insufficiency of ART.

Drug Resistance Mutation Frequency of Single-Genome Amplification-Derived HIV-1 Polymerase Genomes in the Cerebrospinal Fluid and Plasma of HIV-1-Infected Individuals under Nonsuppressive Therapy.

HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (P = 0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7 = 43%). Two HAND subjects (2/7 = 29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n = 4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on nonsuppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the central nervous system (CNS) can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts.IMPORTANCE Several antiretroviral agents do not efficiently enter the CNS, and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We used single-genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 polymerase genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on nonsuppressive cART, and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.

Differences in cytokine and chemokine profiles in cerebrospinal fluid caused by the etiology of cryptococcal meningitis and tuberculous meningitis in HIV patients.

The roles of cytokines and chemokines in HIV-associated cryptococcal meningitis (HCM) and HIV-associated tuberculous meningitis (HTBM) are debatable. In sum, 34 HIV-infected patients without meningitis, 44 HCM patients and 27 HTBM patients were enrolled for study. The concentrations of 22 cytokines/chemokines in cerebrospinal fluid (CSF) were assayed at admission. Principal component analysis (PCA), Pearson's and logistic regression analyses were used to assess the role of cytokines/chemokines in HCM and HTBM. We found the levels of T helper (Th)17, Th1 [interleukin (IL)-12p40, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and TNF-ß and Th2 (IL-2/4/5/6/10)] cytokines were elevated in patients with meningitis compared with those in HIV-infected patients without central nervous system (CNS) infection. Furthermore, the IL-1Ra, IL-12p40, IL-17α and monocyte chemotactic protein-1 (MCP-1) levels were higher in HCM patients, while the IFN-γ, regulated upon activation, normal T cell expressed and secreted (RANTES) and interferon-inducible protein-10 (IP)-10 levels were higher in HTBM patients. Elevated CSF concentrations of IL-17a, TNF-ß, IL-5, IL-12p40 and IL-1Rα were closely related to meningitis, but elevated IP-10, MCP-1, RANTES and IFN-γ levels and CSF white blood cells (WBCs) were protective factors against HCM. Our study suggested that HIV-infected patients with low CSF WBCs have a high risk of HCM. Th1, Th2 and Th17 cytokines/chemokines mediate differences in the pathogenesis of HCM and TBM. Overexpressed proinflammatory MCP-1, RANTES, IFN-γ and IP-10 in CSF are protective factors against HCM but not HTBM.

Modeling HIV-1 infection in the brain.

While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence.

Untargeted GC/TOFMS unravel metabolic profiles in cerebrospinal fluid of Chinese people living with HIV.

BACKGROUND: Metabolic syndrome becomes a focus of clinical cares to people living with HIV (PLHIV) globally. This study aimed to explore the metabolic profiles in cerebrospinal fluid (CSF) of Chinese people living with HIV (PLHIV). METHODS: Cerebrospinal fluid samples from PLHIV and healthy controls were collected from our hospital. Then, the metabolic profiles of CSFs were analyzed PLHIV with healthy individual as the normal controls using the untargeted GC/TOFMS. Following this, kyoto encyclopedia of genes and genomes annotation and pathway analysis were performed to further explore the underlying mechanism of these metabolic alterations in cognitive impairment of PLHIV. RESULTS: Both PCA analysis and OPLS-DA had presented that most samples were localized in 95% CI and the gap between control and HIV could significantly separate from each other. Upon this quality control, a total of 82 known metabolites were identified in CSF between PLHIV and healthy controls. Clustering of these metabolites presented that these differentially expressed metabolites could markedly distinguish HIV from healthy controls. Further pathway analyses showed that TCA cycle (citric acid, fumaric acid, lactate, et al.), amino acid (arginine, proline, alanine, aspartate, glutamine, et al.), lipid (cholesterol, butyrate, et al.) metabolisms were significantly changed in CSF of PLHIV, which might affect the cognitive status of PLHIV via affecting neuron energy support, signaling transduction, and neuroinflammation. CONCLUSION: Metabolic profiles were significantly altered in CSF and might play key roles in the etiology of cognitive impairment of PHLIV. Further explore the exact mechanism for these metabolic changes might be useful for cognitive impairment management of PHLIV.

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.

Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial.

BACKGROUND: Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy. METHODS: EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%. RESULTS: Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, -100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level. CONCLUSION: In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART. CLINICAL TRIALS REGISTRATION: NCT02551523.

Proteomic analysis of cerebrospinal fluid extracellular vesicles reveals synaptic injury, inflammation, and stress response markers in HIV patients with cognitive impairment.

BACKGROUND: Extracellular vesicles (EVs) are nano-sized particles present in most body fluids including cerebrospinal fluid (CSF). Little is known about CSF EV proteins in HIV+ individuals. Here, we characterize the CSF EV proteome in HIV+ subjects and its relationship to neuroinflammation, stress responses, and HIV-associated neurocognitive disorders (HAND). METHODS: CSF EVs isolated from 20 HIV+ subjects with (n = 10) or without (n = 10) cognitive impairment were characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting, and untargeted LC/MS/MS mass spectrometry. Functional annotation was performed by gene ontology (GO) mapping and expression annotation using Biobase Transfac and PANTHER software. Cultured astrocytic U87 cells were treated with hydrogen peroxide for 4 h to induce oxidative stress and EVs isolated by ultracentrifugation. Selected markers of astrocytes (GFAP, GLUL), inflammation (CRP), and stress responses (PRDX2, PARK7, HSP70) were evaluated in EVs released by U87 cells following induction of oxidative stress and in CSF EVs from HIV+ patients by immunoblotting. RESULTS: Mass spectrometry identified 2727 and 1626 proteins in EV fractions and EV-depleted CSF samples, respectively. CSF EV fractions were enriched with exosomal markers including Alix, syntenin, tetraspanins, and heat-shock proteins and a subset of neuronal, astrocyte, oligodendrocyte, and choroid plexus markers, in comparison to EV-depleted CSF. Proteins related to synapses, immune/inflammatory responses, stress responses, metabolic processes, mitochondrial functions, and blood-brain barrier were also identified in CSF EV fractions by GO mapping. HAND subjects had higher abundance of CSF EVs and proteins mapping to GO terms for synapses, glial cells, inflammation, and stress responses compared to those without HAND. GFAP, GLUL, CRP, PRDX2, PARK7, and HSP70 were confirmed by immunoblotting of CSF EVs from subjects with HAND and were also detected in EVs released by U87 cells under oxidative stress. CONCLUSIONS: These findings suggest that CSF EVs derived from neurons, glial cells, and choroid plexus carry synaptic, immune/inflammation-related, and stress response proteins in HIV+ individuals with cognitive impairment, representing a valuable source for biomarker discovery.

Semaphorin4A causes loss of mature oligodendrocytes and demyelination in vivo.

BACKGROUND: Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI. METHODS: Human cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice. RESULTS: Here, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia. CONCLUSIONS: Taken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.

Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals.

We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (ß = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.

Cerebrospinal Fluid Concentrations of the Synaptic Marker Neurogranin in Neuro-HIV and Other Neurological Disorders.

PURPOSE OF REVIEW: The aim of this study was to examine the synaptic biomarker neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF neurogranin in other neurodegenerative diseases. RECENT FINDINGS: CSF concentrations of neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1ß and IL-8. CSF neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.

Neurosyphilis.

Neurosyphilis is caused by the bacterium Treponema pallidum subspecies pallidum (T. pallidum). The organism gains entry into the central nervous system (CNS) early (primary syphilis or chancre phase) in the course of infection. While most patients are able to mount an immune response that effectively clears CNS invasion without long-term complications, a minority go on to develop asymptomatic or symptomatic neurosyphilis. Neurosyphilis has been divided into early and late stages. The early stages include asymptomatic meningitis, symptomatic meningitis, gumma, and meningovascular syphilis, while the late stages include dementia paralytica and tabes dorsalis. Ocular and otologic syphilis can occur at any time but often accompany the acute meningitis of early neurosyphilis. The diagnosis of symptomatic neurosyphilis requires meeting clinical, serologic, and cerebrospinal fluid (CSF) criteria, while the diagnosis of asymptomatic neurosyphilis relies on serologic and CSF criteria alone. In the last several decades, a persistent rise in syphilitic meningitis and other forms of early neurosyphilis have been seen in the human immunodeficiency virus-positive population, principally in men who have sex with men. This article reviews the clinical presentation, diagnosis, and treatment of neurosyphilis, and it addresses the controversy regarding the role of lumbar puncture early in the course of infection.