Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and ...psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.
Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. ...Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.
To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.
Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).
National U.S. multicenter study.
Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.
Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.
Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.
Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 95% CI, 0.73 to 1.66;
> 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 16.2% versus 46 10.9%, respectively;
= 0.026).
The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.
This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.
Bill & Melinda Gates Foundation.
Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce ...the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings.
Between November 5, 2012, and January 5, 2015, we enrolled and followed 1,013 heterosexual HIV-1-serodiscordant couples in Kenya and Uganda in a prospective implementation study. ART and PrEP were offered through a pragmatic strategy, with ART promoted for all couples and PrEP offered until 6 mo after ART initiation by the HIV-1 infected partner, permitting time to achieve virologic suppression. One thousand thirteen couples were enrolled, 78% of partnerships initiated ART, and 97% used PrEP, during a median follow-up of 0.9 years. Objective measures of adherence to both prevention strategies demonstrated high use (≥85%). Given the low HIV-1 incidence observed in the study, an additional analysis was added to compare observed incidence to incidence estimated under a simulated counterfactual model constructed using data from a prior prospective study of HIV-1-serodiscordant couples. Counterfactual simulations predicted 39.7 HIV-1 infections would be expected in the population at an incidence of 5.2 per 100 person-years (95% CI 3.7-6.9). However, only two incident HIV-1 infections were observed, at an incidence of 0.2 per 100 person-years (95% CI 0.0-0.9, p < 0.0001 versus predicted). The use of a non-concurrent comparison of HIV-1 incidence is a potential limitation of this approach; however, it would not have been ethical to enroll a contemporaneous population not provided access to ART and PrEP.
Integrated delivery of time-limited PrEP until sustained ART use in African HIV-1-serodiscordant couples was feasible, demonstrated high uptake and adherence, and resulted in near elimination of HIV-1 transmission, with an observed HIV incidence of <0.5% per year compared to an expected incidence of >5% per year.
Type III IFNs (IFN-lambda/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs ...after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN-lambda was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28Ralpha-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR(-/-)) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA(-/-) and IFNAR(-/-) mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-alphabeta expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-lambda expression, whereas IL-28Ralpha signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28Ralpha only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-lambda and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.
Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.
In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial ...conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.
Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4–6) in HCQ, 6 days (95% CI=4–8) in HCQ/AZ, and 8 days (95% CI=6–10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01–2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63–1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57–1.45, p = 0.70).
Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.
The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
Trial registration ClinicalTrials.gov number NCT04354428
Members of the platelet-derived growth factor (PDGF) ligand family are known to play important roles in wound healing and fibrotic disease. We show that both transient and stable expression of PDGF-C ...results in the development of liver fibrosis consisting of the deposition of collagen in a pericellular and perivenular pattern that resembles human alcoholic and nonalcoholic fatty liver disease. Fibrosis in PDGF-C transgenic mice, as demonstrated by staining and hydroxyproline content, is preceded by activation and proliferation of hepatic stellate cells, as shown by collagen, α-smooth muscle actin and glial fibrillary acidic protein staining and between 8 and 12 months of age is followed by the development of liver adenomas and hepatocellular carcinomas. The hepatic expression of a number of known profibrotic genes, including type β1 TGF, PDGF receptors α and β, and tissue inhibitors of matrix metalloproteinases-1 and -2, increased by 4 weeks of age. Increased PDGF receptor α and β protein levels were associated with activation of extracellular regulated kinase-1 and -2 and protein kinase B. At 9 months of age, PDGF-C transgenic mice had enlarged livers associated with increased fibrosis, steatosis, cell dysplasia, and hepatocellular carcinomas. These studies indicate that hepatic expression of PDGF-C induces a number of profibrotic pathways, suggesting that this growth factor may act as an initiator of fibrosis. Moreover, PDGF-C transgenic mice represent a unique model for the study of hepatic fibrosis progressing to tumorigenesis.
T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called ...interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
HIV risk perception may influence the use of HIV prevention interventions. Using data from HIV-negative adults enrolled in a study of pre-exposure prophylaxis (PrEP) and antiretroviral therapy for ...HIV-serodiscordant couples in Kenya and Uganda, we examined associations between: (1) condom use and risk perception and (2) risk perception and PrEP adherence. Two-thirds of HIV-negative partners reported condomless sex with their HIV-positive partner or another partner in the month prior to study enrollment. Compared to those who reported no condomless sex, participants who reported condomless sex during the month prior to study visit had fivefold higher odds of reporting “high risk” vs “no risk” perception (36.3 versus 10.9%: aOR 4.9, 95% CI 3.4–6.9). Reporting condomless sex in the most recent sex act was associated with increased odds of perceiving some HIV risk (aOR for high risk = 7.3, 95% CI 4.9–10.8; aOR for moderate risk = 4.8, 95% CI 3.5–6.7; aOR for low risk = 3.5, 95% CI 2.7–4.6). We found no significant association between risk perception and PrEP adherence. Sexual behavior aligned with perceived HIV risk, which can facilitate an HIV-negative individual’s decisions about PrEP use.
Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies.
...Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through
CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition.
Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (
= 11); TFV-only (
= 11); or placebo (
= 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 interquartile range (IQR), 36-90. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs.
, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml 95% CI 473, 726 and 87 pg/ml 95% CI 64, 119, respectively).
TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR.
NCT03762382 https://clinicaltrials.gov/ct2/show/NCT03762382.
B cells are important in the development of autoimmune disorders by mechanisms
involving disregulated polyclonal B-cell activation, production of pathogenic
antibodies, and co-stimulation of ...autoreactive T cells. zTNF4 (BLyS, BAFF,
TALL-1, THANK) is a member of the tumour necrosis
factor (TNF) ligand family that is a potent co-activator of B cells in
vitro and in vivo. Here we identify two receptors
for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease.
Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms
characteristic of systemic lupus erythaematosus (SLE) and expand a rare population
of splenic B-1a lymphocytes. In addition, circulating zTNF4 is more abundant
in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of
SLE. We have identified two TNF receptor family members, TACI
and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with
soluble TACI-Ig fusion protein inhibits the development of proteinuria
and prolongs survival of the animals. These findings demonstrate the involvement
of zTNF4 and its receptors in the development of SLE and identify TACI-Ig
as a promising treatment of autoimmune disease in humans.
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