Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection.

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.

Risk of Multiple Sclerosis in People Living with HIV: An International Cohort Study.

OBJECTIVE: There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population. METHODS: Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1 year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada = April 1, 1992 and Sweden = January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada = March 31, 2020 and Sweden = December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated. RESULTS: The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI] = 0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI = 0.31-0.96). INTERPRETATION: This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2024;95:487-494.

Cardiovascular events following coronavirus disease 2019 vaccination in adults: a nationwide Swedish study.

BACKGROUND AND AIMS: While the rationale for coronavirus disease 2019 (COVID-19) vaccination is to reduce complications and overall mortality, some cardiovascular complications from the vaccine itself have been demonstrated. Myocarditis and pericarditis are recognized as rare acute adverse events after mRNA vaccines in young males, while evidence regarding other cardiovascular events remains limited and inconsistent. This study assessed the risks of several cardiovascular and cerebrovascular events in a Swedish nationwide register-based cohort. METHODS: Post-vaccination risk of myocarditis/pericarditis, dysrhythmias, heart failure, myocardial infarction, and cerebrovascular events (transient ischaemic attack and stroke) in several risk windows after each vaccine dose were assessed among all Swedish adults (n = 8 070 674). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) compared with unvaccinated were estimated from Cox regression models adjusted for potential confounders. RESULTS: For most studied outcomes, decreased risks of cardiovascular events post-vaccination were observed, especially after dose three (HRs for dose three ranging from .69 to .81), while replicating the increased risk of myocarditis and pericarditis 1-2 weeks after COVID-19 mRNA vaccination. Slightly increased risks, similar across vaccines, were observed for extrasystoles [HR 1.17 (95% CI 1.06-1.28) for dose one and HR 1.22 (95% CI 1.10-1.36) for dose two, stronger in elderly and males] but not for arrhythmias and for transient ischaemic attack [HR 1.13 (95% CI 1.05-1.23), mainly in elderly] but not for stroke. CONCLUSIONS: Risk of myopericarditis (mRNA vaccines only), extrasystoles, and transient ischaemic attack was transiently increased after COVID-19 vaccination, but full vaccination substantially reduced the risk of several more severe COVID-19-associated cardiovascular outcomes, underscoring the protective benefits of complete vaccination.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

BACKGROUND: To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). METHODS: Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. RESULTS: SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, ß2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. CONCLUSIONS: We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction.

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction.

A Capture-Recapture-based Ascertainment Probability Weighting Method for Effect Estimation With Under-ascertained Outcomes.

Outcome under-ascertainment, characterized by the incomplete identification or reporting of cases, poses a substantial challenge in epidemiologic research. While capture-recapture methods can estimate unknown case numbers, their role in estimating exposure effects in observational studies is not well established. This paper presents an ascertainment probability weighting framework that integrates capture-recapture and propensity score weighting. We propose a nonparametric estimator of effects on binary outcomes that combines exposure propensity scores with data from two conditionally independent outcome measurements to simultaneously adjust for confounding and under-ascertainment. Demonstrating its practical application, we apply the method to estimate the relationship between health care work and coronavirus disease 2019 testing in a Swedish region. We find that ascertainment probability weighting greatly influences the estimated association compared to conventional inverse probability weighting, underscoring the importance of accounting for under-ascertainment in studies with limited outcome data coverage. We conclude with practical guidelines for the method's implementation, discussing its strengths, limitations, and suitable scenarios for application.

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.

Sociodemographic differences in the response to changes in COVID-19 testing guidelines.

During the coronavirus disease 2019 (COVID-19) pandemic, Sweden emphasized voluntary guidelines over mandates. We exploited a rapid change and reversal of the Public Health Agency of Sweden's COVID-19 testing guidelines for vaccinated and recently infected individuals as a quasi-experiment to examine sociodemographic differences in the response to changes in pandemic guidelines. We analyzed daily polymerase chain reaction tests from 1 October 2021 to 15 December 2021, for vaccinated or recently infected adults (≥20 years; n = 1 596 321) from three Swedish regions (Stockholm, Örebro, and Dalarna). Using interrupted time series analysis, we estimated abrupt changes in testing rates at the two dates when the guidelines were changed (1 November and 22 November). Stratified analysis and meta-regression were employed to explore sociodemographic differences in the strength of the response to the guideline changes. Testing rates declined substantially when guideline against testing of vaccinated and recently infected individuals came into effect on 1 November [testing rate ratio: 0.50 (95% confidence interval, CI 0.41, 0.61)], and increased again from these lowered levels by a similar amount upon its reversal on 22 November [testing rate ratio: 2.19 (95% CI: 1.69, 2.85)]. Being Sweden-born, having higher household income, or higher education, were all associated with a stronger adherent response to the guideline changes. Adjusting for stratum-specific baseline testing rates and test-positivity did not influence the results. Our findings suggest that the population was responsive to the rapid changes in testing guidelines, but with clear sociodemographic differences in the strength of the response.

Sweden surpasses the UNAIDS 95-95-95 target: estimating HIV-1 incidence, 2003 to 2022.

BackgroundSweden reached the UNAIDS 90-90-90 target in 2015. It is important to reassess the HIV epidemiological situation due to ever-changing migration patterns, the roll-out of PrEP and the impact of the COVID-19 pandemic.AimWe aimed to assess the progress towards the UNAIDS 95-95-95 targets in Sweden by estimating the proportion of undiagnosed people with HIV (PWHIV) and HIV incidence trends.MethodsWe used routine laboratory data to inform a biomarker model of time since infection. When available, we used previous negative test dates, arrival dates for PWHIV from abroad and transmission modes to inform our incidence model. We also used data collected from the Swedish InfCareHIV register on antiretroviral therapy (ART).ResultsThe yearly incidence of HIV in Sweden decreased after 2014. In part, this was because the fraction of undiagnosed PWHIV had decreased almost twofold since 2006. After 2015, three of four PWHIV in Sweden were diagnosed within 1.9 and 3.2 years after infection among men who have sex with men and in heterosexual groups, respectively. While 80% of new PWHIV in Sweden acquired HIV before immigration, they make up 50% of the current PWHIV in Sweden. By 2022, 96% of all PWHIV in Sweden had been diagnosed, and 99% of them were on ART, with 98% virally suppressed.ConclusionsBy 2022, about half of all PWHIV in Sweden acquired HIV abroad. Using our new biomarker model, we assess that Sweden has reached the UNAIDS goal at 96-99-98.

Early unrecognised SARS-CoV-2 introductions shaped the first pandemic wave, Sweden, 2020.

BackgroundDespite the unprecedented measures implemented globally in early 2020 to prevent the spread of SARS-CoV-2, Sweden, as many other countries, experienced a severe first wave during the COVID-19 pandemic.AimWe investigated the introduction and spread of SARS-CoV-2 into Sweden.MethodsWe analysed stored respiratory specimens (n = 1,979), sampled 7 February-2 April 2020, by PCR for SARS-CoV-2 and sequenced PCR-positive specimens. Sequences generated from newly detected cases and stored positive specimens February-June 2020 (n = 954) were combined with sequences (Sweden: n = 730; other countries: n = 129,913) retrieved from other sources for Nextstrain clade assignment and phylogenetic analyses.ResultsTwelve previously unrecognised SARS-CoV-2 cases were identified: the earliest was sampled on 3 March, 1 week before recognised community transmission. We showed an early influx of clades 20A and 20B from Italy (201/328, 61% of cases exposed abroad) and clades 19A and 20C from Austria (61/328, 19%). Clade 20C dominated the first wave (20C: 908/1,684, 54%; 20B: 438/1,684, 26%; 20A: 263/1,684, 16%), and 800 of 1,684 (48%) Swedish sequences formed a country-specific 20C cluster defined by a spike mutation (G24368T). At the regional level, the proportion of clade 20C sequences correlated with an earlier weighted mean date of COVID-19 deaths.ConclusionCommunity transmission in Sweden started when mitigation efforts still focused on preventing influx. This created a transmission advantage for clade 20C, likely introduced from ongoing cryptic spread in Austria. Therefore, pandemic preparedness should have a comprehensive approach, including capacity for large-scale diagnostics to allow early detection of travel-related cases and community transmission.

Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology.

Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.

Longitudinal decline of plasma neurofilament light levels after antiretroviral initiation in people living with HIV.

BACKGROUND: This retrospective follow-up study aims to investigate the dynamic longitudinal change of plasma neurofilament light (NfL) levels after antiretroviral therapy (ART) initiation in a cohort of people living with human immunodeficiency virus (HIV) (PWH). METHODS: We tested a convenience sample of 116 patients from the NORTHIV study. Plasma NfL levels-measured using Single molecule array (Simoa) technology-as well as other laboratory parameters were collected at baseline, weeks 4, 48, 96, and 144. Linear mixed-effects models were estimated to evaluate longitudinal change over time. Baseline CD4+ T-cell levels, CDC classification, and HIV RNA levels were considered. Models were adjusted by age, sex, treatment regimen, and baseline serum creatinine levels. RESULTS: Plasma NfL levels were higher at baseline and also declined faster during the follow-up for participants with CD4+ count <100 cells/µl compared with >100 cells/µl. No significant difference was found between the CD4+ strata 100-199 and 200-499/µl. Participants with CDC classification stages B and C had higher levels of plasma NfL at baseline, as well as faster decline compared with participants with stage A. No significant main effects or change over time was found in baseline HIV RNA levels, treatment regimen, or sex. CONCLUSION: Plasma NfL is a sensitive biomarker to assess ongoing central nervous system injury in PWH. Plasma NfL concentrations decline relatively fast following ART initiation and then stabilize after 48 weeks. Plasma NfL concentrations are associated with CD4+ count and stage of HIV disease. No correlations were seen with different ART regimens.

Plasmablasts in previously immunologically naïve COVID-19 patients express markers indicating mucosal homing and secrete antibodies cross-reacting with SARS-CoV-2 variants and other beta-coronaviruses.

Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin ß1, only some integrin ß7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients.

COVID-19 hospitalization outcomes in adults by HIV status; a nation-wide register-based study.

OBJECTIVES: To assess the outcome of patients hospitalized with COVID-19 by HIV status and risk factors for severe COVID-19 in people living with HIV (PWH), we performed a nationwide cohort study using register data. METHODS: All people aged ≥18 years hospitalized with a primary COVID-19 diagnosis (U07.1 or U07.2) in Sweden between February 2020 and October 2021 were included. The primary outcome was severe COVID-19 [intensive care unit (ICU) admission or 90-day mortality]. Secondary outcomes were days in hospital and ICU, complications in hospital, and risk factors for severe COVID-19 in PWH. Regression analyses were performed to assess severe COVID-19 by HIV status and risk factors. RESULTS: Data from 64 815 hospitalized patients were collected, of whom 121 were PWH (0.18%). PWH were younger (p < 0.001), and larger proportions were men (p = 0.014) and migrants (p < 0.001). Almost all PWH had undetectable HIV-RNA (93%) and high CD4 T-cell counts (median = 560 cells/µL, interquartile range: 376-780). In an unadjusted model, PWH had statistically significant lower odds of severe COVID-19 compared with patients without HIV [odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.34-0.94], but there was no significant difference after adjusting for age and comorbidity (adjusted OR = 0.7, 95% CI: 0.43-1.26). A statistically significant lower proportion of PWH (8%, 95% CI: 5-15%) died within 90 days compared with those without HIV (16%, 95% CI: 15-16%, p = 0.024). There was no statistically significant difference in days in hospital and complications during the hospital stay between PWH and patients without HIV. CONCLUSIONS: In this nationwide study including well-treated PWH, HIV was not a risk factor in hospitalized patients for developing severe COVID-19.

Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection.

INTRODUCTION: CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). METHODS: This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. RESULTS: In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04). CONCLUSIONS: The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.

COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity.

Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.

Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium: analysis from a randomised placebo-controlled trial.

HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain-derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-ß). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer's Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/ß), Aß38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389-651) cells/µL. Biomarker concentrations between groups did not differ at baseline. However, both groups' blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

The molecular epidemiology of HIV-1 in Sweden 1996 to 2022, and the influence of migration from Ukraine.

BackgroundThe global distribution of HIV-1 subtypes is evolving, which is reflected in the Swedish HIV cohort. The subtype HIV-1A6, which may be prone to developing resistance to cabotegravir, is the most common subtype in Ukraine.AimWe aimed to examine trends in HIV-1 subtype distribution in Sweden, with a special focus on HIV-1A6, and to describe the virology, demography and treatment of Ukrainian people living with HIV (PLWH) who migrated to Sweden in 2022.MethodsData about PLWH in Sweden are included in a national database (InfCareHIV). We used the online tool COMET to establish HIV-1 subtypes and the Stanford database to define drug resistance mutations. We investigated the relation between virological characteristics and demographic data.ResultsThe early epidemic was predominated by HIV-1 subtype B infections in people born in Sweden. After 1990, the majority of new PLWH in Sweden were PLWH migrating to Sweden, resulting in an increasingly diverse epidemic. In 2022, HIV-1A6 had become the sixth most common subtype in Sweden and 98 of the 431 new PLWH that were registered in Sweden came from Ukraine. We detected HIV RNA in plasma of 32 Ukrainian patients (34%), of whom 17 were previously undiagnosed, 10 had interrupted therapy and five were previously diagnosed but not treated. We found HIV-1A6 in 23 of 24 sequenced patients.ConclusionThe molecular HIV epidemiology in Sweden continues to diversify and PLWH unaware of their HIV status and predominance of HIV-1A6 should be considered when arranging care directed at PLWH from Ukraine.

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.