Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox.

Mpox represents a persistent health concern with varying disease severity. Reinfections with mpox virus (MPXV) are rare, possibly indicating effective memory responses to MPXV or related poxviruses, notably vaccinia virus (VACV) from smallpox vaccination. We assessed cross-reactive and virus-specific CD4+ and CD8+ T cells in healthy individuals and mpox convalescent donors. Cross-reactive T cells were most frequently observed in healthy donors over 45 years. Notably, long-lived memory CD8+ T cells targeting conserved VACV/MPXV epitopes were identified in older individuals more than four decades after VACV exposure and exhibited stem-like characteristics, defined by T cell factor-1 (TCF-1) expression. In mpox convalescent donors, MPXV-reactive CD4+ and CD8+ T cells were more prevalent than in controls, demonstrating enhanced functionality and skewing toward effector phenotypes, which correlated with milder disease. Collectively, we report robust effector memory MPXV-specific T cell responses in mild mpox and long-lived TCF-1+ VACV/MPXV-specific CD8+ T cells decades after smallpox vaccination.

Impact of pre-antiretroviral treatment HIV-RNA on time to successful virological suppression and subsequent virological failure - two nationwide, population-based cohort studies.

BACKGROUND: The impact of pre-antiretroviral treatment (ART) HIV-RNA on time to successful virological suppression and subsequent failure in HIV patients remains poorly investigated. METHODS: We used the Swedish InfCareHIV database and the Danish HIV Cohort Study to evaluate impact of pre-ART HIV-RNA on primary virological suppression (HIV-RNA < 50 copies/ml) and risk of secondary virological failure (two consecutive HIV-RNA > 200 copies/ml or one >1000 copies/ml). The study included 3366 Swedish and 2050 Danish ART naïve individuals who initiated ART in the period 2000-2018. We used Kaplan-Meier estimates and Cox regression analyses to estimate absolute risks and hazard ratios. RESULTS: In both cohorts, more than 95% of patients with a pre-ART HIV-RNA <100 000 copies/ml obtained virological suppression within the first year after ART initiation contrasting 74% (Sweden) and 86% (Denmark) in those with HIV-RNA >1 000 000 copies/ml. Almost all patients obtained virological suppression after four years irrespective of pre-ART HIV-RNA. In contrast, we observed no substantial impact of pre-ART HIV-RNA on risk of virological failure once virological suppression was obtained. CONCLUSION: High pre-ART HIV-RNA is strongly associated with increased time to successful virological suppression, but pre-ART HIV-RNA has no impact on risk of subsequent virological failure.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity.

The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolomics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a substantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and personalized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as α-ketoglutarate, succinate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.

Associations between HIV viremia during antiretroviral therapy and cardiovascular disease.

OBJECTIVE: To investigate the association between HIV viremia exposure during antiretroviral therapy (ART) and cardiovascular disease (CVD) risk. DESIGN: Nationwide observational cohort. METHODS: Participants (age >15 years) from the Swedish nationwide InfCareHIV register initiating ART 1996-2017 were categorized in a time-updated manner into four viremia categories, starting from 12 months after ART initiation: suppression (<50 copies/ml), low-level viremia (50-199 copies/ml and 200-999 copies/ml, respectively), and high-level viremia (≥1000 copies/ml). In addition, cumulative viremia was estimated as the area under the log viral load (VL) curve. Proportional subhazard models adjusted for sex, age, pre-ART CD4 and VL, injection drug use, and country of birth were used to analyze the association between viremia exposure and CVD risk (ischemic heart disease, stroke, and heart failure; data obtained by linkage to national registers), accounting for the competing risk of non-CVD death. RESULTS: In all, 337 cases of CVD were observed during 44 937 person-years of follow-up ( n  = 6562). Higher viremia exposure was associated with CVD, both when parameterized as cumulative viremia (adjusted subhazard ratio [aSHR] per 1 log 10  copy × year/ml, 1.03; 95% confidence interval [CI], 1.01-1.05) and as viremia category (aSHR for high-level viremia versus suppression, 1.45; 95% CI, 1.03-2.05). We observed no association between CVD and low-level viremia compared with those with suppression. CONCLUSIONS: Higher exposure to HIV viremia was linked to CVD in ART recipients, whereas no increased risk was detected for people with low-level viremia compared with viral suppression. Causal inference is limited by the observational nature of this study.

Factors associated with low-level viraemia in people with HIV starting antiretroviral therapy: A Swedish observational study.

OBJECTIVE: Low-level viraemia (LLV) occurs in some people with HIV (PWH) receiving antiretroviral therapy (ART) and has been linked to inferior treatment outcomes. We investigated factors associated with LLV in a nationwide cohort of Swedish PWH starting ART. METHODS: Participants were identified from the InfCareHIV register, with the following inclusion criteria: ART initiation 2006-2017, age >15 years, ≥4 viral load (VL) results available and no documented treatment interruptions or virologic failure (≥2 consecutive VL ≥200 copies/ml) during follow-up. Starting from 6 months after ART initiation, participants were followed for 24 months and categorised as viral suppression (VS; VL <50 copies/ml) or LLV (≥2 consecutive VL 50-199 copies/ml). We analysed the association between the following factors and LLV using multivariable logistic regression: sex, age, pre-ART VL and CD4 count, ART regimen, country of birth, HIV-1 subtype and transmission category. RESULTS: Among 3383 participants, 3132 (92.6%) had VS and 251 (7.4%) had LLV. In univariable analyses, factors associated with LLV were male sex, higher age, lower pre-ART CD4 count, higher pre-ART VL and ART regimen. After adjustment, the following factors were associated with LLV (adjusted odds ratio; 95% confidence interval): male sex (1.6; 1.1-2.3), higher pre-ART VL (2.7; 2.2-3.3), pre-ART CD4 count <200 cells/µl (1.6; 1.2-2.2), protease inhibitor (PI)-based regimen (1.5; 1.1-2.1), non-standard ART (2.4; 1.0-5.5) and injecting drug use (2.0; 1.1-3.7). CONCLUSION: Among Swedish PWH, LLV during ART was associated with markers of HIV disease severity before starting ART, male sex, injecting drug use and use of PI-based or non-standard ART regimens.

Metabolic Perturbation Associated With COVID-19 Disease Severity and SARS-CoV-2 Replication.

Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, glucose transporter 1, in CD8+ T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

Associations Between Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid Levels and Incidence of Invasive Cancer in People With HIV After Initiation of Combination Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus (HIV) viremia could be involved in the increased risk of cancer in people with HIV (PWH) receiving combination antiretroviral therapy (cART). We analyzed the association between plasma HIV ribonucleic acid levels in PWH starting cART and incident invasive cancer using the Swedish cohort InfCare HIV linked with national registers. METHODS: Adults starting cART in 1996-2017 were included if they had ≥1 viral load (VL) measurement before receiving any antiretroviral agent (pre-ART VL) and ≥2 VLs ≥6 months after start of cART. Viremia during cART was analyzed both as viremia-copy-years and categorized as suppression (<50 copies/mL), low-level viremia ([LLV] 50-999 copies/mL), and nonsuppression (≥1000 copies/mL). The main outcome was a composite of invasive malignancies with increased incidence among PWH. We fitted proportional subhazard models (including sex, age, pre-ART CD4 count, and injection drug use) for both pre-ART VL and viremia during cART. RESULTS: After 32 105 person-years, 3254 of 4931 participants (66%) were classified as suppressed, 438 (9%) were classified as LLV, and 1221 (25%) were classified as nonsuppressed. Neither viremia category nor cumulative viremia during cART had a statistically significant association with cancer. Higher pre-ART VL was associated with cancer (adjusted subhazard ratio, 1.4; 95% confidence interval, 1.0-1.8); this remained statistically significant with viremia during cART in the model. In subanalysis, the association with pre-ART VL was statistically significant for acquired immune deficiency syndrome (AIDS)-defining and infection-related non-AIDS-defining cancer, but not for other malignancies. CONCLUSIONS: In this nationwide cohort, pre-ART VL was an independent predictor of invasive cancer, whereas viremia profile during cART was not associated with cancer incidence.

Higher plasma drug levels in elderly people living with HIV treated with darunavir.

BACKGROUND: The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged ≥ 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and side-effects in PLHIV aged ≥ 65 years of age, with controls ≤ 49 years of age. METHODS: Patients ≥ 65 years of age and controls ≤ 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. RESULTS: Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (≤ 49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). CONCLUSIONS: Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged ≥ 65 years of age, compared to controls ≤ 49 years of age.

All-Cause Mortality and Serious Non-AIDS Events in Adults With Low-level Human Immunodeficiency Virus Viremia During Combination Antiretroviral Therapy: Results From a Swedish Nationwide Observational Study.

BACKGROUND: The impact of low levels of human immunodeficiency virus (HIV) RNA (low-level viremia [LLV]) during combination antiretroviral therapy (cART) on clinical outcomes is unclear. We explored the associations between LLV and all-cause mortality, AIDS, and serious non-AIDS events (SNAEs). METHODS: We grouped individuals starting cART 1996-2017 (identified from the Swedish InfCare HIV register) as virologic suppression (VS; <50 copies/mL), LLV (repeated viral load, 50-999 copies/mL), and nonsuppressed viremia (NSV; ≥1000 copies/mL). Separately, LLV was subdivided into 50-199 and 200-999 copies/mL (reflecting different definitions of virologic failure). Proportional-hazard models (including sex, age, pre-ART CD4 count and viral load, country of birth, injection drug use, treatment experience and interruptions, and an interaction term between viremia and time) were fitted for the study outcomes. RESULTS: A total of 6956 participants were followed for a median of 5.7 years. At the end of follow-up, 60% were categorized as VS, 9% as LLV, and 31% as NSV. Compared with VS, LLV was associated with increased mortality (adjusted hazard ratio [aHR], 2.2; 95% confidence interval [CI], 1.3-3.6). This association was also observed for LLV 50-199 copies/mL (aHR, 2.2; 95% CI, 1.3-3.8), but was not statistically significant for LLV 200-999 copies/mL (aHR, 2.1; 95% CI, .96-4.7). LLV 50-999 copies/mL was not linked to increased risk of AIDS or SNAEs, but in subanalysis, LLV 200-999 copies/mL was associated with SNAEs (aHR, 2.0; 95% CI, 1.2-3.6). CONCLUSIONS: In this population-based cohort, LLV during cART was associated with adverse clinical outcomes.

HMGB1 in severe soft tissue infections caused by Streptococcus pyogenes.

Extracellular High Mobility Group Box 1 (HMGB1) has been associated with acute and chronic inflammatory conditions. However, little is known about HMGB1 in necrotizing bacterial infections. We hypothesized that the local HMGB1 response is excessive in severe soft tissue infections (STIs), which are characterized by necrosis and hyperinflammation. To explore this, tissue biopsies were collected from patients with varying severity of Streptococcus pyogenes skin and STIs, including erysipelas, cellulitis, and necrotizing fasciitis. Tissue sections were immunostained for HMGB1, S. pyogenes, and inflammatory cell infiltrates and results quantified by acquired computerized image analysis (ACIA). HMGB1 expression increased in parallel to disease severity and was significantly higher in necrotizing fasciitis than in erysipelas (p = 0.0023). Confocal microscopy of sections co-stained for HMGB1 and cell markers revealed both extracellular and cytoplasmic HMGB1, the latter of which was found predominantly in macrophages. To further verify macrophages as main source of activation triggered HMGB1 release, human macrophages were infected with clinical S. pyogenes isolates. The results demonstrated infection triggered release of HMGB1. Dual staining's visualized HMGB1 in areas close to, but not overlapping, with neutrophils, indicating a potential chemotactic role. In vitro transmigration experiments showed a chemotactic effect of HMGB1 on neutrophils. The data furthermore provided in vivo support that HGMB1 may form immunostimulatory complexes with IL-1ß. Taken together, the findings provide the first in vivo evidence that HMGB1 is abundant at the local site of severe bacterial STIs and its levels correlated to severity of infections; hence, indicating its potential value as a biomarker for tissue pathology.

Short- and long-term mortality in severe sepsis/septic shock in a setting with low antibiotic resistance: a prospective observational study in a Swedish university hospital.

BACKGROUND: There is little epidemiologic data on sepsis, particularly in areas of low antibiotic resistance. Here we report a prospective observational study of severe sepsis and septic shock in patients admitted to the Intensive Care Unit (ICU) at Karolinska University Hospital, Sweden. We aimed to evaluate short- and long-term mortality, and risk factors for sepsis-related death. A second aim was to investigate patient care in relation to gender. METHODS: One hundred and one patients with severe sepsis and septic shock, admitted to the ICU between 2005 and 2009, were prospectively enrolled in the study. Defined primary endpoints were day 28, hospital, and 1-year mortality. Risk factors for sepsis-related death was evaluated with a multivariate analysis in a pooled analysis with two previous sepsis cohorts. In the subset of patient admitted to the ICU through the emergency department (ED), time to clinician evaluation and time to antibiotics were assessed in relation to gender. RESULTS: In the septic cohort, the day 28, hospital, and 1-year mortality rates were 19, 29, and 34%, respectively. Ninety-three percent of the patients received adequate antibiotics from the beginning. Multi-resistant bacteria were only found in three cases. Among the 43 patients admitted to the ICU through the ED, the median time to antibiotics was 86 min (interquartile range 52-165), and overall 77% received appropriate antibiotics within 2 h. Female patients received antibiotics significantly later compared to male patients (p = 0.047). CONCLUSION: The results demonstrate relatively low mortality rates among ICU patients with severe sepsis/septic shock, as compared to reports from outside Scandinavia. Early adequate antibiotic treatment and the low incidence of resistant isolates may partly explain these findings. Importantly, a gender difference in time to antibiotic therapy was seen.

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

INTRODUCTION: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed. METHODS: A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden. RESULTS: Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥ 17 and suPAR ≥ 12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥ 12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥ 17 and suPAR ≥ 12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort. CONCLUSIONS: A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock.

INTRODUCTION: Rapid detection of, and optimized treatment for, severe sepsis and septic shock is crucial for successful outcome. Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in the plasma of patients with severe sepsis and septic shock in the ICU. METHODS: A prospective study was conducted of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. A total of 179 patients was included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission. RESULTS: HBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of ≥ 15 ng/mL and/or a HBP (ng/mL)/white blood cell count (109/L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n = 151) and in the whole group (n = 179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days. CONCLUSIONS: Plasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with a non-septic illness in the ICU. HBP was associated with severity of disease and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis. Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections.

Neutrophil-derived hyperresistinemia in severe acute streptococcal infections.

The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections.

Pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock.

OBJECTIVE: Resistin induces insulin resistance in mice. In humans, recent data suggest that resistin functions as a proinflammatory cytokine. Here, we studied resistin up to 2 wks after admission in patients with septic shock and/or severe sepsis. DESIGN: Two prospective studies of patients with sepsis and in vitro studies of resistin interaction with monocytes. SETTING: Intensive care unit at Karolinska University Hospital and Center for Infectious Medicine, Karolinska Institute, Huddinge, Sweden. PATIENTS: Twenty-nine patients with severe sepsis and 66 with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-five patients were studied, 25 of whom died within 28 days. Resistin and cytokine levels and routine biochemistry were measured at three to six defined time points during the first 2 wks after admission and were correlated to other cytokines, glucose levels, body mass index, Acute Physiology and Chronic Health Evaluation II, and Sepsis-related Organ Failure Assessment scores. Serum resistin was significantly elevated compared with healthy controls (p < .000001) and correlated with severity of disease as measured by Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores, with an increasingly strong degree of correlation over time. Median levels were four- to eight-fold higher than controls and remained high up to 2 wks after admission to the intensive care unit. Levels correlated with interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, creatinine, D-dimer, and lactate, but not with p-glucose or body mass index. In vitro, resistin was released from monocytes after stimulation with either lipopolysaccharide or high mobility group box 1 protein. Recombinant resistin itself up-regulated intercellular adhesion molecule-1 on monocytes. CONCLUSIONS: This is the first study assessing systemic levels of resistin in patients with septic shock/severe sepsis. We show that resistin is a marker of severity of disease and possibly a mediator of the prolonged inflammatory state seen in infected critically ill patients. Further exploration of resistin as a therapeutic target and marker of disease is merited.

HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages.

High mobility group box protein 1 (HMGB1) is an abundant component of mammalian cells that can be released into extracellular milieu actively or by cells that undergo necrosis. Exposure of inflammatory and endothelial cells to HMGB1 leads to the release of cytokines, including TNF-alpha and IL-6. To evaluate the impact of exogenous HMGB1 on viral replication in HIV-1 infected cells, we studied models of latent and acute infection. Extracellular HMGB1 dose dependently increased HIV-1 replication in the monocytic cells, U1, which is an established model for studying latent HIV-1 infection. Dexamethasone, a known inhibitor of NF-kappaB signaling in U1 cells, inhibited HMGB1-induced stimulation of the viral production. Addition of HMGB1 to primary monocytic cells with active HIV-1 infection elicited the opposite effect, due to suppression of the viral replication. The mechanism of this unexpected finding was explained by an HMGB1-mediated increased release of chemokines (RANTES, MIP-1alpha, and MIP-1beta) that are known to inhibit HIV-1 replication. The stimulatory effect of the HMGB1 was not present when latently infected T-cells (ACH-2) were used as target cells. Our data suggest that extracellular HMGB1 has a dichotomic effect on the HIV-1 infection in monocytes but not in lymphocytes. Both activation of latent HIV-1 infection and inhibition of active replication can thus be seen in vitro.

The role of high mobility group box-1 protein in severe sepsis.

PURPOSE OF REVIEW: Despite medical advances, mortality in severe sepsis remains high. As our understanding of the innate immune system has expanded, clinical trials have focused on inhibiting cytokines present early in the infectious process such as interleukin-1 and tumor necrosis factor-alpha, although with disappointing results. There is evidence that the nuclear protein high mobility group box-1 protein, when released extracellularly, acts as a persistent mediator of sepsis and is therefore a promising candidate for therapeutic intervention. This review summarizes current knowledge of the protein and highlights recent relevant findings. RECENT FINDINGS: High mobility group box-1 protein may be released into the circulation either due to necrosis of cells or by active release from macrophages and endothelial cells. Models of experimental sepsis in mice have shown a strong association between extracellular high mobility group box-1 protein and lethality. Treatments against the biological activities of high mobility group box-1 protein reduce lethality in these models. Other studies have shown high mobility group box-1 protein as a key regulator in acute and chronic inflammation. Recent findings confirm that high mobility group box-1 protein is persistently elevated in human patients with severe sepsis. SUMMARY: Despite all efforts, mortality in severe sepsis remains high. A massive amount of evidence indicates high mobility group box-1 protein as a delayed and important propagator of inflammation. Recent studies confirm persisting high levels of high mobility group box-1 protein in serum up to 1 week after hospitalization. Reducing levels of the protein by anti-high mobility group box-1 protein treatment may be one way to moderate uncontrolled inflammation seen in sepsis.

Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock.

OBJECTIVE: To study the systemic release and kinetics of high mobility group box-1 protein (HMGB1) in relation to clinical features in a population of patients with severe sepsis or septic shock and to compare these with the kinetics of the cytokines interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha. DESIGN: Prospective study of two cohorts of patients. SETTING: Intensive care unit and infectious disease clinic at Karolinska University Hospital Huddinge. PATIENTS: Twenty-six patients with severe sepsis, 33 patients with septic shock, and a reference group of five patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-four patients were included, ten of whom died within 28 days. Cytokine levels were measured at five time points during the first week after admission and were correlated to Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Two HMGB1 assays were used. Both demonstrated delayed kinetics for HMGB1 with high levels on inclusion that remained high throughout the study period. Serum concentration at 144 hrs, the last sampling point, was 300 times higher, 34,000 +/- 76,000 pg/mL (mean +/- sd), than any of the other cytokines. This study, however, found no predictable correlation between serum levels of HMGB1 and severity of infection. We did quite unexpectedly find significantly lower levels of HMGB1 in nonsurvivors compared with survivors as measured by our main assay, but the other showed no difference between the two groups. Levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha correlated significantly with severity of disease, and all were significantly higher in patients with septic shock compared with those with severe sepsis. Neither of these comparisons showed significant correlations for HMGB1. CONCLUSIONS: This is the first prospective study assessing the release over time of HMGB1 in a population of patients with sepsis, severe sepsis, or septic shock. Levels remained high in the majority of patients up to 1 wk after admittance, indicating that the cytokine indeed is a downstream and late mediator of inflammation. Further studies are required to fully define the relationship of HMGB1 to severity of disease.

Molecular mechanisms and biological importance of Plasmodium falciparum erythrocyte rosetting

Rosetting, i.e. the spontaneous binding of uninfected to malaria infected erythrocytes and endothelial cytoadherence may hinder the blood flow and lead to serve Plasmodium falciparum malaria. Falciparum isolates obtained from unconscious patients all form rosettes and/or express a significantly higher man rosetting rate than isolates from patients with uncomplicated malaria. Furthermore, sera of patients with cerebral malaria are devoid of anti-rosetting activity while sera from patients with mild disease carry high levels of anti-rosetting antibodies. The presence of anti-rosetting antibodies also seems important for the efficient interaction of rosetting infected rbc and leucocytes. Two parasite derived rosetting ligands of Mr 22k and Mr28K named "rosettins, have been found on the surface of rosetting infected erythrocytes. CD36 has in at least some strains of parasites been found to function as a rosetting receptor on the uninfectederythrocyte. Heparin disrupts rosettes of P. falciparum in vitro and inhibits the sequestration of rosetting cells ex vivo. In conclusion, rosetting seems a crucial factor in the development of cerebral malaria and treatment of patients with anti-rosetting substances might become an effectivew adjunct in the treatment of severe malaria