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A 54-year-old man with treated HIV developed a subacute deterioration of speech, mobility and cognition. Cerebrospinal fluid (CSF) analysis showed a raised protein and a discordant CSF HIV RNA paired with plasma HIV RNA, confirming the diagnosis of CSF HIV RNA escape syndrome. It is important to consider this diagnosis in people with treated HIV who develop new neurological symptoms., Competing Interests: Competing interests: JU has received honoraria for participation in advisory boards and preparing non-promotional educational materials for Gilead Sciences, GSK and ViiV Healthcare., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

It is debated whether CNS involvement begins during acute human immunodeficiency virus (HIV) infection in persons without meningitis/encephalitis and whether specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir; darunavir; or both) during primary HIV infection were enrolled. Serum and CSF were collected at baseline and at 12 and 48 (serum only) weeks after treatment initiation. Single molecule array was used to measure neurofilament light chain (NFL), total tau protein (Tau), brain-derived neurotrophic factor, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase. We assessed the longitudinal change in biomarkers over time, in addition to the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/ml if 5-18 years, 10 pg/ml if 18-51 years, 15 pg/ml if 51-61 years, 20 pg/ml if 61-70 years and 35 pg/ml if >70 years). Serum was available from 47 participants at all time points, and CSF was available from 13 participants at baseline and 7 at Week 12. We observed a significant direct serum-to-CSF correlation for NFL (ρ = 0.692, P = 0.009), GFAP (ρ = 0.659, P = 0.014) and brain-derived neurotrophic factor (ρ = 0.587, P = 0.045). Serum (ρ = 0.560, P = 0.046) and CSF NFL (ρ = 0.582, P = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (P = 0.006) and GFAP (P = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and four participants (30.8%), respectively; considering serum NFL, this proportion was lower at Weeks 12 (31.9%, P = 0.057) and 48 (27.7%, P = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis; however, its clinical implications remain unclear. We analyzed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into < 100 mg/dl (72%, n = 641) and ≥ 100 mg/dl (28%, n = 249). We described baseline clinical variables and 18-week mortality by CSF protein groups. Those with CSF protein ≥ 100 mg/dl were more likely to present with Glasgow coma scale score < 15 (P < .01), self-reported seizures at baseline (P = .02), higher CD4 T-cell count (P < .001), and higher CSF white blood cells (P < .001). Moreover, those with a baseline CSF protein ≥ 100 mg/dl also had a lower baseline CSF fungal burden (P < .001) and a higher percentage of sterile CSF cultures at day 14 (P = .02). Individuals with CSF protein ≥ 100 mg/dl demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules, pro-inflammatory cytokines, T-helper cell type 1 and 17 cytokines, and immune-exhaustion marker (P < .05). 18-week mortality risk in individuals with a CSF protein < 100 mg/dl was 34% higher (unadjusted Hazard Ratio 1.34; 95% Confidence Interval, 1.05-1.70; P = .02) than those with CSF protein ≥ 100 mg/dl. In HIV-associated cryptococcal meningitis, individuals with baseline CSF protein ≥ 100 mg/dl more frequently presented with neurological symptoms, higher CSF inflammatory cytokines, reduced fungal burden, and lower mortality risk. The findings underscore the prognostic significance of baseline CSF protein levels in predicting disease severity and mortality risk in cryptococcal meningitis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Signatures of neurodegeneration in clinical samples from a subject with multiple sclerosis (MS) acutely infected with HIV were investigated with single-cell transcriptomics using 10X Chromium technology. Sequencing was carried out on NovaSeq-TM, and the analysis was performed with Cell Ranger software (v 7.1.0) associated with a specifically established bioinformatic pipeline. A total of 1446 single-cell transcriptomes in cerebrospinal fluid (CSF) and 4647 in peripheral blood mononuclear cells (PBMCs) were obtained. In the CSF, many T-cell lymphocytes with an enriched amount of plasma cells and plasmacytoid dendritic (pDC) cells, as compared to the PBMCs, were detected. An unsupervised cluster analysis, putting together our patient transcriptomes with those of a publicly available MS scRNA-seq dataset, showed up-regulated microglial neurodegenerative gene expression in four clusters, two of which included our subject's transcriptomes. A few HIV-1 transcripts were found only in the CD4 central memory T-cells of the CSF compartment, mapping to the gag-pol , vpu , and env regions. Our data, which describe the signs of neurodegenerative gene expression in a very peculiar clinical situation, did not distinguish the cause between multiple sclerosis and HIV infection, but they can give a glimpse of the high degree of resolution that may be obtained by the single-cell transcriptomic approach.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology., Competing Interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). These organizations and companies had no role in the study design, data collection, decision to publish, or publication of the manuscript. MG has received research grants from Gilead Sciences and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi. These organizations and companies had no role in the study design, data collection, decision to publish, or publication of the manuscript., (Copyright: © 2024 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human Herpesviruses (HHVs) play a significant role in neurological diseases such as encephalitis and meningitis, adding significant morbidity. This study aims to retrospectively analyze the effect of HHVs on patients with neurological symptoms, focusing on the Herpesviridae family's contributions to central nervous system (CNS) infections., Methods: This retrospective cohort study included 895 patients suspected of viral CNS infections, utilizing molecular diagnosis via qPCR to identify HHVs in cerebrospinal fluid (CSF) samples. This was conducted at a reference tertiary care hospital for infectious diseases in the western Brazilian Amazon from January 2015 to December 2022, focusing on the Herpesviridae family's clinical repercussions and of Cytomegalovirus in CNS infections., Results: The findings revealed that 7.5% of the analyzed samples tested positive for HHVs, with Human Cytomegalovirus (HCMV) and Epstein-Barr Virus (EBV) being the most prevalent. A significant association was found between HHVs and neurological diseases such as encephalitis and meningitis, especially among people living with HIV/AIDS (PLWHA), highlighting the opportunistic nature of these viruses. The study underscores the critical role of CSF analysis in diagnosing CNS infections and the complexity of managing these infections in HIV patients due to their immunocompromised status., Conclusions: The results emphasize the need for comprehensive diagnostic approaches and tailored treatment strategies for CNS infections in immunocompromised individuals. The study calls for ongoing research and advancements in clinical practice to improve patient outcomes facing CNS infections, particularly those caused by HHVs.

Introduction: Human Immunodeficiency virus (HIV) is effectively suppressed in the blood by the Antiretroviral Therapy in people living with HIV, but in rare cases can be present in some tissues and body fluids. In recent years, integrated systems were validated for detecting HIV-1 in plasma or serum. but not in cerebrospinal fluid (CSF). We evaluated the performance of ELITE InGenius® in comparison with the cobas® in this area., Methods: To test the diagnostic accuracy of the HIV-1 ELITe MGB® kit on CSF samples, we tested CSF samples previously characterised with the cobras® HIV1 test. Archived CSF samples were also spiked with serial dilutions of the 4th WHO International Standard for HIV-1 NAT and assays and tested to assess the repeatability and reproducibility of the ELITechGroup assay., Results: The HIV-1 ELITe MGB® Kit confirmed all the HIV-1 negative CSF samples from patients HIV positive in plasma and from non-HIV1 patients. All the CSF samples that were HIV-1 positive by the cobas®, were confirmed positive by the ELITe InGenius®. Concordance across the methods was also observed when processing the CSF dilutions spiked at medium-low titre, mimicking HIV-1 low-load infections., Conclusions: The two systems were equivalent in the detection and quantification of HIV-1 RNA in CSF samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low CD4-expressing cells, such as microglia. We examined HIV-1 RNA concentration, co-receptor usage, and CSF compartmentalization in paired CSF and blood samples from 19 adults not on treatment. Full-length envelope CSF- and plasma-derived reporter viruses were generated from 3 subjects and phenotypically characterized in human primary CD4 +  T-cells and primary microglia. Median HIV RNA levels were higher in plasma than in CSF (5.01 vs. 4.12 log10 cp/mL; p = 0.004), and coreceptor usage was mostly concordant for CCR5 across the paired samples (n = 17). Genetically compartmentalized CSF viral populations were detected in 2 subjects, one with and one without neurological symptoms. All viral clones could replicate in T-cells (R5 T cell-tropic). In addition, 3 CSF and 1 plasma patient-derived viral clones also had the capacity to replicate in microglia/macrophages and, therefore have an intermediate macrophage tropic phenotype. Overall, with this study, we demonstrate that in a subset of PLWH, plasma-derived viruses undergo genetic and phenotypic evolution within the CNS, indicating viral infection and replication in CNS cells. It remains to be studied whether the intermediate macrophage-tropic phenotype observed in primary microglia represents a midpoint in the evolution towards a macrophage-tropic phenotype that can efficiently replicate in microglial cells and propagate viral infection in the CNS., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024 British HIV Association.)

We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p ​= ​0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p ​= ​0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes., Competing Interests: Declaration of competing interest VCM has received investigator-initiated research grants (to the institution) and consultation fees from Eli Lilly, Bayer, Gilead Sciences, and ViiV. The other authors had nothing to declare., (Published by Elsevier Inc.)

Background: Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immunomodulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH., Methods: Cross-sectional single-center (United States) analysis in 184 PWH on ART with plasma HIV RNA < 200 copies/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and clinical conditions., Results: Participants were mostly middle-aged men, with median CD4+ T cells of 620/µL. In adjusted models, SSRI use was associated with 3 PCs: higher CSF and plasma Aβ42 and CSF CCL2 (aβ=.14, P = .040); lower CSF 8-oxo-dG, total tau, and sCD14 (aβ=-.12, P = .042); and higher plasma sCD14 with lower sCD40L (aβ=.15, P = .042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aβ=.22, P = .004). Statins and ACEIs showed no association., Conclusions: SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation, and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2024 John Wiley & Sons Ltd.)

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/mm 3 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/mm 3 , 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/mm 3 , 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., (© 2024. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. We performed a case-control study of asymptomatic (AS) escape and NS escape subjects with HIV-negative subjects as controls in which we investigated differential immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape subjects. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV envelope and gag proteins in the CSF of AS and NS escape subjects. Whether these additional inflammatory markers are byproducts of an HIV-driven process or whether they independently contribute to the neuropathogenesis of NS escape will require further study., Competing Interests: Declaration of Competing Interest Dr. Joseph DeRisi has received grants from the Chan Zuckerberg Biohub, personal fees from the Public Health Company and from Allen & Company; Dr. Michael Wilson has received unrelated grants from Roche/Genentech and Novartis as well as speaking honoraria from Novartis, Takeda, WebMD and Genentech. Drs. Wilson and DeRisi serve as co-founders and advisors for Delve Bio. Dr. Christopher Bartley has received an honorarium for speaking to the Commonwealth Club and owns shares in NowRx Inc. M. Gisslen has received research grants from Gilead Sciences and Janssen-Cilag and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi, all unrelated to the content of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Plasma C-X-C-motif chemokine ligand-13 (CXCL13) has been linked to disease progression and mortality in people living with HIV (PLWH) and is a candidate target for immune-based strategies for HIV cure. Its role in central nervous system (CNS) of PLWH has not been detailed. We described CSF CXCL13 levels and its potential associations with neurological outcomes. Cross-sectional study enrolling PLWH without confounding for CXCL13 production. Subjects were divided according to CSF HIV-RNA in undetectable (< 20 cp/mL) and viremics. CSF CXCL13, and biomarkers of blood-brain barrier (BBB) impairment, intrathecal synthesis, and immune activation were measured by commercial immunoturbidimetric and ELISA assays. All subjects underwent neurocognitive assessment. Sensitivity analyses were conducted in subjects with intact BBB only. 175 participants were included. Detectable CSF CXCL13 was more common in the viremic (31.4%) compared to the undetectable group (13.5%; OR 2.9 [1.4-6.3], p = 0.006), but median levels did not change (15.8 [8.2-91.0] vs 10.0 [8.1-14.2] pg/mL). In viremics (n = 86), CXCL13 associated with higher CSF HIV-RNA, proteins, neopterin, intrathecal synthesis and BBB permeability. In undetectable participants (n = 89), CXCL13 associated with higher CD4+T-cells count, CD4/CD8 ratio, CSF proteins, neopterin, and intrathecal synthesis. The presence of CXCL13 in the CSF of undetectable participants was associated with increased odds of HIV-associated neurocognitive disorders (58.3% vs 28.6%, p = 0.041). Sensitivity analyses confirmed all these findings. CXCL13 is detectable in the CSF of PLWH that show increased intrathecal IgG synthesis and immune activation. In PLWH with CSF viral suppression, CXCL13 was also associated with neurocognitive impairment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022. Journal of NeuroVirology, Inc.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Monocytes and macrophages activation are crucial in human immunodeficiency virus (HIV) central nervous system (CNS) infection and HIV associated neurocognitive disorders (HAND) pathogenesis. The soluble form of CD14 (sCD14) is a marker of monocyte activation. We hypothesized that sCD14 levels would be lower in people with HIV-1 subtype C (HIV-1C) than in HIV-1B owing to a variant Tat cysteine dimotif (C30S31) with reduced chemotactic activity. A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH); 27 samples of the HIV-1B subtype and 40 of the non-B HIV-1 subtypes (including 26,HIV-1C), and 18 HIV-negative controls were included. sCD14 levels were quantified using a high-sensitivity enzyme-linked immunosorbent assay. sCD14 increase in serum, but not in CSF, was higher in samples from HIV-1B than HIV-1C (p = 0.002; Cohen's d, 0.7). CSF or serum sCD14 values were not correlated with global deficit score or specific cognitive domains. The impact of HIV-1 on monocyte stimulation biomarkers evaluated by sCD14 in serum was subtype-dependent, higher in HIV-1B than HIV-1C, consistent with reduced chemotactic activity as hypothesized., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S)., Methods: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and β2 microglobulin (β2m) in the CSF and serum were quantified using different immunoassays., Results: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum β2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and β2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum β2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024)., Discussion: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to determine the capacity of HIV in the blood and cerebrospinal fluid of patients, depending on the reception of antiretroviral therapy (ART). Paired blood and cerebrospinal fluid samples were examined in 116 HIV-infected patients to determine the level of viral load in both biological fluids and the number of blood CD4+ lymphocytes. In patients receiving ART, the difference between the load of HIV in blood and cerebrospinal fluid (CSF) was significantly smaller than in untreated patients. Taking ART reduces the amount of HIV in the blood and CSF, but the dynamics of virus suppression in these biological fluids differ. The analysis revealed a statistically significant inverse relationship between the load of HIV in the blood and the number of CD4+ lymphocytes in untreated patients. There is a clear moderate positive correlation between the level of viremia and the clinical stage of HIV infection, as well as the duration of the disease. The number of CD4+ lymphocytes was expected to be inversely weakly correlated with the clinical stage of HIV infection and its duration. Accordingly, a direct correlation of mean strength was found between the levels of viral load in the blood and cerebrospinal fluid. There was a significant increase in the difference between the levels of HIV load in the blood and CSF compared with the average value in 25.6% of patients., (© 2022 JOURNAL of MEDICINE and LIFE.)

People living with HIV (PLWH) age with an excess burden of comorbidities that may increase the incidence of age-related complications. There is controversy surrounding the hypothesis that HIV can accelerate neurodegeneration and Alzheimer's dementia (AD). We performed a retrospective study to analyze the distribution of cerebrospinal fluid (CSF) AD biomarkers (beta amyloid 1-42 fragment, tau, and phosphorylated tau) in adult PLWH (on cART with undetectable viremia, n = 136, with detectable viremia, n = 121, and with central nervous system CNS disorders regardless of viremia, n = 72) who underwent a lumbar puncture between 2008 to 2018; HIV-negative controls with AD were included ( n = 84). Five subjects (1.5%) presented CSF biomarkers that were compatible with AD: one was diagnosed with AD, whereas the others showed HIV encephalitis, multiple sclerosis, cryptococcal meningitis, and neurotoxoplasmosis. Regardless of confounders, 79.6% of study participants presented normal CSF AD biomarkers. Isolated abnormalities in CSF beta amyloid 1-42 (7.9%) and tau (10.9%) were associated with age, biomarkers of intrathecal injury, and inflammation, although no HIV-specific feature was associated with abnormal CSF patterns. CSF levels of AD biomarkers very poorly overlapped between HIV-positive clinical categories and AD controls. Despite the correlations with neurocognitive performance, the inter-relationship between amyloid and tau proteins in PLWH seem to differ from that observed in AD subjects; the main driver of the isolated increase in tau seems represented by non-specific CNS inflammation, whereas the mechanisms underlying isolated amyloid consumption remain unclear.

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, β-amiloid 42 , neopterin, S100β), 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., (© 2022. Journal of NeuroVirology, Inc.)

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-β 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-β, 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., (© 2021 British Society for Immunology.)

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: The authors have declared that no competing interests exist. Author Ntombi Ntshuba was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.

HIV-1 is responsible for the development of a spectrum of cognitive impairments known as HIV-associated neurocognitive disorder (HAND). In the era of antiretroviral therapy (ART), HAND remains prevalent in people living with HIV (PLWH), despite low or undetectable viral loads. Persistent neuroinflammation likely plays an important role in the contributing biological mechanisms. Multiple cerebrospinal fluid (CSF) immune markers have been studied but it is unclear which markers most consistently correlate with neurocognitive impairment. We therefore conducted a systematic review of studies of the association of CSF immune markers with neurocognitive performance in ART-experienced PLWH. We aimed to synthesize the published data to determine consistent findings and to indicate the most noteworthy CSF markers of HAND. Twenty-nine studies were included, with 20 cross-sectional studies and 9 longitudinal studies. From the group of markers most often assayed, specific monocyte activation (higher levels of Neopterin, sCD163, sCD14) and neuroinflammatory markers (higher levels of IFN-γ, IL-1α, IL-7, IL-8, sTNFR-II and lower levels of IL-6) showed a consistent direction in association with HIV-associated neurocognitive impairment. Furthermore, significant differences exist in CSF immune markers between HIV-positive people with and without neurocognitive impairment, regardless of viral load and nadir/current CD4 + count. These markers may be useful in furthering our understanding of the neuropathology, diagnosis and prognosis of HAND. Studies using prospective designs (i.e. pre- and post-interventions), "multi-modal" methods (e.g. imaging, inflammation and neurocognitive evaluations) and utilizing a combination of the markers most commonly associated with HAND may help delineate the mechanisms of HAND., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control., Methods: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau., Findings: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls., Competing Interests: The authors have no competing interests that influenced the contents of this paper. However, the authors list the following general potential conflicts of interest: RWP had been a consultant to Merck and Co and had received an honorarium and travel support from AbbVie and Gilead Sciences for meeting presentations during part of the time of sample collections. MG has received research grants from Abbott, Baxter, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche and Tibotec, and he has received honoraria as a speaker and/or scientific advisor from Abbott/Abbvie, Amgen, Biogen, Bioinvent, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer, Roche and Tibotec. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Spudich has received an honorarium and travel support from AbbVie, Inc. for a meeting presentation. BLS has received research grants from Gilead Sciences, and an honorarium and travel support from Merck. SMK, SSS, VA, SS, CDG, DF, LH, JP, PJN, BLS and CTY report no conflicts. In no case were the above-listed activities related directly to the submitted work—neither to the conceptualization, study design, data collection, analysis, or manuscript preparation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Even in the era of suppressive antiretroviral therapy, people with HIV (PWH) suffer greater exposure to inflammation than their uninfected peers. Although poor social support and social isolation have been linked to systemic inflammation in the general population, it is not known whether this is true also among PWH., Methods: People with and without HIV infection were enrolled in a community-based, single-center study. Primary predictors were the Medical Outcomes Study Social Support Survey, and outcomes were a panel of inflammatory biomarkers (ICAM-1, MCP-1, IL-6, IL-8, IP-10, C-reactive protein, D-dimer, VEGF, sCD14, and uPAR) in blood plasma and cerebrospinal fluid (CSF)., Results: PWH had worse positive social support (P = 0.0138) and affectionate support (P = 0.0078) than did HIV- individuals. A factor analysis was used to group the biomarkers into related categories separately for each fluid. Levels of 3 of the 4 plasma factors were significantly higher in PWH than HIV- (ps = 0.007, 0.001, and 0.0005, respectively). Levels of 1 of the 3 CSF factors also were significantly higher in PWH than HIV- (P = 0.0194). In the combined PWH and HIV- cohort, poorer social support was associated with higher levels of a factor in plasma loading on MCP-1, IL-8, and VEGF (P = 0.020) and with a CSF factor loading on MCP-1 and IL-6 (P = 0.006)., Conclusion: These results suggest that enhancing social support might be an intervention to reduce inflammation and its associated adverse outcomes among PWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Surrogate markers of HIV central nervous system (CNS) persistence are needed because direct HIV measurements from the CNS require specialized protocols and are not always detectable or quantifiable. We analyzed paired plasma and CSF samples from people with HIV (PWH) on suppressive therapy (ART) with a validated HIV single copy RNA assay. Two potential markers of CNS persistence were measured (CXCL10 and sCD30). We then examined associations with CSF HIV RNA positivity in univariable and multivariable analyses. Among 66 individuals, 18.2% had detectable CSF HIV. Individuals who had detectable HIV in CSF had higher CSF CXCL10 concentrations (median 514 pg/ml versus median 317 pg/ml, p = 0.019), but did not have significantly different CSF sCD30 concentrations (median 7.5 ng/ml versus median 7.6 ng/ml, p = 0.78). In the multiple logistic analysis, both higher CSF CXCL10 (p = 0.038) and plasma HIV detectability (p = 0.035) were significantly associated with detectable CSF HIV. Both sCD30 and CXCL10 correlated positively with NfL and NSE, two neuronal markers. This study demonstrates that CSF CXCL10 concentrations reflect low level HIV CNS persistence despite virologic suppression on ART. Given that it is readily detectable and quantifiable, this chemokine may be a promising biomarker to evaluate HIV eradication therapies that target the CNS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Tuberculous (TB) meningitis (TBM), accounting for 70-80% of cases of neurotuberculosis, is one of the most severe forms of extrapulmonary tuberculosis. Two-thirds of new TB cases come from eight countries. Polymorphisms in toll-interleukin-1 receptor domain and in leukotriene A4 hydrolase (LTA4H) gene, affect the risk of inflammation in TBM. The common site of tuberculoma in children is cerebellum, and they may rarely develop tuberculous encephalopathy which has a high mortality. Young females with a high cerebrospinal fluid (CSF) protein have an increased predisposition to develop optochiasmatic arachnoiditis. Spinal TB meningitis may mimic transverse myelitis or Guillain-Barre syndrome. An extra-neural focus of TB should be sought clinically and radiologically as it may indicate safer and more accessible sites for diagnostic samplings. Cartridge-based nucleic acid amplification test (CBNAAT), also known as Genexpert test, is a polymerase chain reaction (PCR)-based method for detection of TB which also detects rifampicin resistance as it targets the rpob gene of mycobacteria. Line probe assays, based on PCR and reverse hybridization methods, identify mutations associated with drug resistance within a week. TBM being a paucibacillary disease, often evades a definite diagnosis and empirical treatment for a minimum of 9 months is warranted based on clinical judgement. All TBM patients should receive adjunctive corticosteroids, even those with HIV infection. Drug resistance is strongly associated with previous treatment and bedaquiline as well as delamanid have received approvals for multidrug resistant (MDR) TB. The key principle of managing MDR TB is never to add a single drug to a failing regimen. Correct combination and duration of most effective second line drugs in MDR TB require further modifications. Early shunting should be considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the stage of TBM at which treatment has been started.

Background: People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations., Methods: We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods., Results: We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (p values > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272), p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085), p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (ρ = 0.374, p = 0.016) and age (ρ = 0.537, p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL, p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%, p = 0.017] were higher in participants aged > 50 years., Conclusions: We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.

Background: Across many settings, lack of virologic control remains common in people with HIV (PWH) because of late presentation and lack of retention in care. This contributes to neuronal damage and neurocognitive impairment, which remains prevalent. More evidence is needed to understand these outcomes in both PWH and people without HIV (PWOH)., Methods: We recruited PWH initiating antiretroviral therapy and PWOH at 2 sites in the United States. One hundred eight adults were enrolled (56 PWOH and 52 PWH), most of whom had a second assessment at least 24 weeks later (193 total assessments). Tumor necrosis factor alpha, monocyte chemotactic protein-1 (MCP-1), neopterin, soluble CD14, and neurofilament light chain protein (NFL) were measured in plasma and cerebrospinal fluid (CSF). Using multivariate models including Bayesian model averaging, we analyzed factors associated with global neuropsychological performance (NPT-9) and CSF NFL at baseline and over time., Results: At baseline, higher CSF MCP-1 and plasma sCD14 were associated with worse NPT-9 in PWH, while CSF HIV RNA decrease was the only marker associated with improved NPT-9 over time. Among PWH, higher CSF neopterin was most closely associated with higher NFL. Among PWOH, higher CSF MCP-1 was most closely associated with higher NFL. After antiretroviral therapy initiation, decrease in CSF MCP-1 was most closely associated with NFL decrease., Conclusion: Monocyte-associated CSF biomarkers are highly associated with neuronal damage in both PWH and PWOH. More research is needed to evaluate whether therapies targeting monocyte-associated inflammation may ameliorate HIV-associated neurobehavioral diseases.

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., Competing Interests: The authors have declared that no competing interests exist.

Objective: Aim of this study was to compare cerebrospinal fluid (CSF) virological control, biomarkers and neurocognition of neurologically symptomatic patients on dual antiretroviral therapies (dual therapy) vs. 2 nucleoside reverse transcriptase inhibitors-based three-drug regimens (triple therapy)., Design: Retrospective monocentric cross-sectional study., Methods: We analysed data from people living with HIV undergoing lumbar puncture for clinical/research reasons with plasma HIV-RNA less than 200 copies/ml and neurological/neurocognitive symptoms without significant contributing comorbidities. We measured CSF HIV-RNA, inflammation, blood-brain barrier integrity, neuronal damage and astrocytosis biomarkers (five biomarkers by ELISA and five indices by immunoturbidimetry) and recorded the neurocognitive performance (14 tests). CSF escape was defined as any case of CSF HIV-RNA 0.5 Log10 higher than viraemia or any case of detectable CSF HIV-RNA coupled with undetectable viraemia., Results: A total of 78 patients on triple therapy and 19 on dual therapy were included. Overall, 75.3% male, median age 51 years (46-58), current CD4 count 545 cells/μl (349-735), time on current regimens 18 months (8-29), but length of plasma suppression 32 months (14-94). The two groups did not differ in terms of HIV-associated neurological diagnoses, demographic and viro-immunological features. Undetectable CSF HIV-RNA (73.7% in dual therapy vs. 78.2% in triple therapy, p.67) and CSF escape (21.1% in dual therapy vs. 19.2% in triple therapy, p.86) did not differ. No difference was observed in depression, anxiety, neurocognition (in 63 participants) nor in any tested biomarker., Conclusion: In people living with HIV with neurological/neurocognitive symptoms, peripherally effective dual therapy can show CSF virosuppression, inflammation, neuronal and astrocyte integrity and neurocognition comparable to triple therapy.

Background: Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically., Methods: We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups., Results: The PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function., Conclusions: This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

Objective: To determine whether oxidative stress in virologically suppressed people with HIV (PWH) may contribute to or result from neurodegeneration, we measured 7,8-dihydro-8-oxoguanine (8-oxo-dG), a marker of DNA damage due to oxidative stress, and markers of age-related neurodegeneration, specifically, reduced levels of CSF Aβ-42, and elevated CSF total tau and neurofilament light (NFL)., Methods: This cross-sectional study prospectively enrolled participants at 6 US centers in the CNS HIV Antiretroviral Effects Research study. Inclusion criteria included HIV+ with a plasma level of HIV RNA ≤50 copies/mL. Exclusions included significant CNS confounding conditions. Measurements of total tau and Aβ-42 were performed by bead suspension array. NFL and 8-oxo-dG were measured using ELISA., Results: Participants were 53 PWH, mean age 55 (±9.3) years, 19% women, and 48% non-Hispanic White. Higher 8-oxo-dG correlated with markers of AD-related neurodegeneration including lower CSF Aβ-42 (r = -0.34; p = 0.012) and higher CSF NFL (r = 0.39; p = 0.0091) and total tau (r = 0.6696; p < 0.0001). Relationships remained after adjusting for demographic variables. Levels of protein carbonyls, a marker of protein oxidation, were not related to neurodegeneration markers., Conclusions: Among virologically suppressed PWH, nucleic acid oxidation was associated with standard CSF biomarkers of neurodegeneration. Potential sources of oxidative stress in PWH include low-level HIV replication, inflammation, mitochondrial dysfunction, and specific antiretroviral drugs. Results suggest that the higher levels of oxidative stress among PWH may play a role in neurodegeneration., Classification of Evidence: This study provides Class II evidence that among virologically suppressed PWH, nucleic acid oxidation is associated with standard CSF biomarkers of neurodegeneration., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

To determine effects of cryptococcal meningitis (CM) on human immunodeficiency virus (HIV)-1C cerebrospinal fluid (CSF) viral escape, CSF/plasma viral discordance, and drug resistance mutation (DRM) discordance between CSF and plasma compartments, we compared CSF and plasma viral load (VL) and DRMs in individuals with HIV-associated CM in Botswana.This cross-sectional study utilized 45 paired CSF/plasma samples from participants in a CM treatment trial (2014-2016). HIV-1 VL was determined and HIV-1 protease and reverse transcriptase genotyping performed. DRMs were determined using the Stanford HIV database. CSF viral escape was defined as HIV-1 ribonucleic acid ≥0.5 log10 higher in CSF than plasma and VL discordance as CSF VL > plasma VL.HIV-1 VL was successfully measured in 39/45 pairs, with insufficient sample volume in 6; 34/39 (87.2%) participants had detectable HIV-1 in plasma and CSF, median 5.1 (interquartile range: 4.7-5.7) and 4.6 (interquartile range:3.7-4.9) log10 copies/mL, respectively (P≤.001). CSF viral escape was present in 1/34 (2.9%) and VL discordance in 6/34 (17.6%). Discordance was not associated with CD4 count, antiretroviral status, fungal burden, CSF lymphocyte percentage nor mental status. Twenty-six of 45 (57.8%) CSF/plasma pairs were successfully sequenced. HIV-1 DRM discordance was found in 3/26 (11.5%); 1 had I84IT and another had M46MI in CSF only. The third had K101E in plasma and V106 M in CSF.Our findings suggest that HIV-1 escape and DRM discordance may occur at lower rates in participants with advanced HIV-disease and CM compared to those with HIV associated neurocognitive impairment.

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.

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., (Copyright © 2020 American Society for Microbiology.)

Background: The objective was to compare the effect of HIV-1C and HIV-1B subtypes on neurofilament light (NfL) cerebrospinal fluid (CSF) levels and ratios of NfL to tau proteins. Additional comparisons were performed between people with HIV (PWH), participants with Alzheimer disease (AD), and HIV-negative controls (HIV-). We also calculated the diagnostic characteristics of CSF NfL and its ratios in HIV-associated neurocognitive disorder (HAND) diagnosis., Methods: CSF NfL, T-tau, and P-tau181 concentrations were measured using immunoassays in a total of 108 CSF samples, including PWH (n = 68), HIV- (n = 16), and participants with AD (n = 24). These proteins were compared between HIV-1B (n = 27) and HIV-1C (n = 26) using multiple linear regression adjusted for nadir CD4 and plasma viral load suppression. Comparisons between PWH, HIV-, and participants with AD were adjusted for gender and age., Results: CSF neurocytoskeleton proteins and their ratios were comparable in HIV-1B and HIV-1C. However, the HIV-1C group had a higher proportion of samples of CSF NfL above the reference value (n = 14, 53.85%) than the HIV-1B group (n = 8, 29.63%), P = 0.098. The values of CSF NfL were higher in the AD group [2578 (1864; 3500) pg/mL] than those in PWH [683 (500; 1197) pg/mL, P < 0.001] and control [660 (539; 802) pg/mL, P = 0.012] groups. The value of CSF NfL and its ratios for HAND diagnosis were poor., Conclusion: The effects of HIV-1B and HIV-1C on CSF NfL and tau ratios were comparable. The differences in CSF neurocytoskeleton proteins between PWH and individuals with AD suggested they might not share the same mechanisms of impairment. Further research is necessary to evaluate CSF NfL on the differential diagnoses of HAND with AD.

Despite the implementation of effective conjugate vaccines against the three main bacterial pathogens that cause meningitis, Streptococcus pneumoniae , Haemophilus influenzae type b (Hib), and Neisseria meningitidis serogroup A, the burden of meningitis in West Africa remains high. The relative importance of other bacterial, viral, and parasitic pathogens in central nervous system infections is poorly characterized. Cerebrospinal fluid (CSF) specimens were collected from children younger than 5 years with suspected meningitis, presenting at pediatric teaching hospitals across West Africa in five countries including Senegal, Ghana, Togo, Nigeria, and Niger. Cerebrospinal fluid specimens were initially tested using bacteriologic culture and a triplex real-time polymerase chain reaction (PCR) assay for N. meningitidis , S. pneumoniae , and H. influenzae used in routine meningitis surveillance . A custom TaqMan Array Card (TAC) assay was later used to detect 35 pathogens including 15 bacteria, 17 viruses, one fungus, and two protozoans. Among 711 CSF specimens tested, the pathogen positivity rates were 2% and 20% by the triplex real-time PCR (three pathogens) and TAC (35 pathogens), respectively. TAC detected 10 bacterial pathogens, eight viral pathogens, and Plasmodium . Overall, Escherichia coli was the most prevalent (4.8%), followed by S. pneumoniae (3.5%) and Plasmodium (3.5%). Multiple pathogens were detected in 4.4% of the specimens. Children with human immunodeficiency virus (HIV) and Plasmodium detected in CSF had high mortality. Among 220 neonates, 17% had at least one pathogen detected, dominated by gram-negative bacteria. The meningitis TAC enhanced the detection of pathogens in children with meningitis and may be useful for case-based meningitis surveillance.

We examined the relationship between CSF immune cells and neurocognition and neuronal damage in HIV+ individuals before and after initiating antiretroviral therapy. Multivariate analysis at baseline indicated that greater CD4+ T cell abundance was associated with better cognition (p = .017), while higher CSF HIV RNA was associated with increased neuronal damage (p = .014). Following 24 weeks of antiretroviral therapy, CD8+ T cells, HLA-DR expressing CD4+ and CD8+ T cells, B cells, NK cells, and non-classical monocyte percentage decreased in CSF. Female gender was negatively associated with cognitive performance over time, as was higher percentage of HLA-DR expressing CD8+ T cells at baseline., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma., Methods: We measured a panel of proinflammatory cytokines (interleukin [IL]-16, C-reactive protein [CRP], IL-6, interferon gamma-induced protein [IP]-10, soluble CD14, and soluble tumor necrosis factor receptor type II [sTNFRII]) in CSF and blood plasma in PWH and HIV- individuals who did or did not use cannabis at various levels of exposure. Participants in this observational cohort were recruited from community sources and underwent lumbar puncture and phlebotomy. Cannabis use parameters were characterized by self-report based on a semistructured timeline follow-back interview. Cytokines were measured using commercially available immunoassays. Data were analyzed using factor analysis., Results: Participants were 35 PWH and 21 HIV- individuals, mean (SD) age 45.4 (14.5) years, 41 cannabis ever users, and 15 never users. PWH and HIV- were not different in recency, cumulative months, grams, or density of cannabis use. A factor analysis using CSF biomarkers yielded a factor loading on CRP, IL-16, and sTNFRII that was significantly associated with recency of cannabis use (more recent use associated with lower factor 1 values, reflecting less inflammation; r = 0.331 [95% CI 0.0175, 0.586]). In particular, more recent cannabis use was related to lower IL-16 levels (r = 0.549 [0.282, 0.737]). Plasma biomarkers yielded a factor loading on sTNFRII and IP-10 that was associated with more recent cannabis use (more recent use related to less inflammation; r = 0.374 [0.0660, 0.617])., Conclusions: Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)