IL7RA rs10491434 polymorphism is related to spontaneous HIV infection control in naïve HIV-infected patients: A retrospective study.

Interleukin 7 receptor (IL7R) is vital in the adaptive immune response against human immunodeficiency viruses (HIV). We assessed IL7RA polymorphisms (SNPs) in antiretroviral therapy (ART)-naïve HIV patients for their association with spontaneous HIV infection control. We conducted a retrospective cohort study involving 667 ART-naïve patients categorized by HIV progression (ordinal variable): 150 rapid progressors, 334 moderate/typical progressors, 86 long-term nonprogressors elite controllers (LTNPs-EC), and 97 LTNPs-non-EC. We genotyped three IL7RA SNPs using Agena Bioscience's MassARRAY platform. The association between IL7RA SNPs and spontaneous HIV infection control was evaluated using ordinal logistic regression. Individuals carrying the rs10491434 G allele have a higher likelihood of spontaneous HIV infection control (adjusted odds ratio [aOR] = 1.33; p = 0.023). Moreover, the IL7RA GCT haplotype, consisting of three specific SNPs (rs6897932, rs987106, and rs10491434), demonstrated an association with the control of untreated HIV infection (aOR = 1.34; p = 0.050). Remarkably, the rs10491434 SNP and the IL7RA GCT haplotype exhibited similar aOR values, suggesting that rs10491434 may be primarily responsible for the observed effect of the haplotype. IL7RA rs10491434 G allele is associated with a higher likelihood of spontaneous HIV infection control, indicating its significant role in the pathogenesis of HIV, possibly influencing infection course and viral replication control.

Recently acquired hepatitis C: Epidemiological characteristics and treatment response in a large cohort of MSM living with HIV in Madrid.

INTRODUCTION: We analyzed epidemiological, clinical characteristics, and the response to treatment in people living with HIV (PLHIV) who recently acquired hepatitis C (RAHC) in a multicentre study in Madrid (Spain). METHODS: Multicenter, ambispective, observational study of RAHC in men who have sex with men (MSM) infected with HIV. Clinical, epidemiological, and RAHC evolution were recorded prospectively in 2019 and 2020 and retrospectively in 2017 and 2018. In patients who received HCV treatment, sustained virological response (SVR) was provided 12 weeks after the end of treatment in an intention to treat analysis (ITT): all treated patients were included; and in analysis per-protocol (PP): missing patients were excluded. RESULTS: Overall, 133 patients were included. Median (IQR) age was 40 (34.3-46.1) years, 90.9% had at least one previous sexual transmission disease (STD), and 33.6% had previously hepatitis C. More than half of the prospective sample included patients using chemsex related drugs (57.3%), 45.7% of them intravenously. The most prevalent genotype was G1a (66.2%), followed by G4 (11.3%). Ten of 90 patients evaluated for spontaneous cure (11%) cured the infection spontaneously, and 119 had treatment after a median time of 1.8 (0.7-4.6) months: sustained virological response (SVR) was achieved in 90.7% in the ITT and 94.7% in the PP analysis, with no differences regarding the direct-acting antiviral agents (DAA) combination used. CONCLUSIONS: MSM infected by HIV with a RAHC were exposed to high-risk sexual behavior. Spontaneous cure rate was low, while SVR after treatment was achieved by more than 90%.

IgG antibody levels against the SARS-CoV-2 spike protein in mother-child dyads after COVID-19 vaccination.

PURPOSE: We aimed to assess IgG antibodies against the SARS-CoV-2 spike protein (anti-SARS-CoV-2 S IgG) in vaccinated mothers and their infants at delivery and 2-3 months of age. METHODS: We conducted a prospective study on mothers who received at least one dose of the COVID-19 vaccine (Pfizer-BNT162b2, Moderna mRNA-1273, or Oxford-AstraZeneca ChAdOx1-S) during pregnancy and on their infants. The baseline was at the time of delivery (n = 93), and the end of follow-up was 2 to 3 months post-partum (n = 53). Serum anti-SARS-CoV-2 S IgG titers and ACE2 binding inhibition levels were quantified by immunoassays. RESULTS: Mothers and infants had high anti-SARS-CoV-2 S IgG titers against the B.1 lineage at birth. However, while antibody titers were maintained at 2-3 months post-partum in mothers, they decreased significantly in infants (p < 0.001). Positive and significant correlations were found between anti-SARS-CoV-2 S IgG titers and ACE2-binding inhibition levels in mothers and infants at birth and 2-3 months post-partum (r > 0.8, p < 0.001). Anti-S antibodies were also quantified for the Omicron variant at 2-3 months post-partum. The antibody titers against Omicron were significantly lower in mothers and infants than those against B.1 (p < 0.001). Again, a positive correlation was observed for Omicron between IgG titers and ACE2-binding inhibition both in mothers (r = 0.818, p < 0.001) and infants (r = 0.386, p < 0.005). Previous SARS-CoV-2 infection and COVID-19 vaccination near delivery positively impacted anti-SARS-CoV-2 S IgG levels. CONCLUSIONS: COVID-19 mRNA vaccines induce high anti-SARS-CoV-2 S titers in pregnant women, which can inhibit the binding of ACE2 to protein S and are efficiently transferred to the fetus. However, there was a rapid decrease in antibody levels at 2 to 3 months post-partum, particularly in infants.

IRF5-TNOP3 polymorphisms are associated with elite control of HIV infection: A retrospective study.

IRF5-TNPO3 polymorphisms have previously been related to immune response, and TNPO3 plays a role in human immunodeficiency virus (HIV)-1 infection after nuclear import. Therefore, we analyzed the genetic association between IRF5-TNPO3 polymorphisms and the HIV elite control in long-term nonprogressors (LTNPs). We performed a retrospective cohort study on 183 LTNPs, who were antiretroviral therapy-naïve with CD4+ ≥ 500 cells/mm3 , viral load ≤10 000 copies/mL, and asymptomatic over 10 years after HIV seroconversion. The primary outcome variable was HIV elite control (undetectable viral load in at least 90% of the measurements for at least 1 year). Seven IRF5-TNPO3 polymorphisms were genotyped using Agena Bioscience's MassARRAY platform. We found a significant association between specific IRF5-TNPO3 genotypes and HIV elite control: rs2004640 TT (aOR = 2.05; p = 0.041), rs10954213 AA (aOR = 1.95; p = 0.035), rs2280714 TT (aOR = 2.02; p = 0.031), and rs10279821 CC (aOR = 2.12; p = 0.017). We also found a significant association between IRF5-TNPO3 haplotype TATC composed of the favorable significant polymorphisms (rs2004640, rs10954213, rs2280714, and rs10279821) and the HIV elite control (aOR = 1.59; p = 0.048). IRF5-TNPO3 rs2004640, rs10954213, rs2280714, and rs10279821 polymorphisms were related to HIV elite control in LTNPs. Our data provide new knowledge about the impact of IRF5-TNPO3 polymorphisms on HIV pathogenesis to understand the phenomenon of natural HIV control.

Diagnostic performance of hepatitis C core antigen assay to identify active infections: A systematic review and meta-analysis.

Hepatitis C virus (HCV) core antigen (HCVcAg) assay is an alternative for diagnosing HCV infection in a single step. This meta-analysis aimed to evaluate the Abbott ARCHITECT HCV Ag assay's diagnostic performance (validity and utility) for diagnosing active hepatitis C. PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library were searched until 10 January 2023. The protocol was registered at the prospective international register of systematic reviews (PROSPERO: CRD42022337191). Abbott ARCHITECT HCV Ag assay was the test for evaluation, and nucleic acid amplification tests with a cut-off ≤50 IU/mL were the gold standard. Statistical analysis was performed using STATA with the MIDAS module and random-effects models. The bivariate analysis was conducted on 46 studies (18,116 samples). The pooled sensitivity was 0.96 (95% CI = 0.94-0.97), specificity 0.99 (95% CI = 0.99-1.00), positive likelihood ratio 141.81 (95% CI = 72.39-277.79), and negative likelihood ratio 0.04 (95% CI = 0.03-0.06). The area under the summary receiver operating characteristic curve was 1.00 (95% CI = 0.34-1.00). For active hepatitis C prevalence values of 0.1%-15%, the probability that a positive test was a true positive was 12%-96%, respectively, indicating that a confirmatory test should be necessary, particularly with a prevalence ≤5%. However, the probability that a negative test was a false negative was close to zero, indicating the absence of HCV infection. The validity (accuracy) of the Abbott ARCHITECT HCV Ag assay for screening active HCV infection in serum/plasma samples was excellent. Although the HCVcAg assay showed limited diagnostic utility in low prevalence settings (≤1%), it might help diagnose hepatitis C in high prevalence scenarios (≥5%).

Diagnostic Performance of the HCV Core Antigen Test To Identify Hepatitis C in HIV-Infected Patients: a Systematic Review and Meta-Analysis.

The standard algorithm for diagnosing hepatitis C virus (HCV) infection has two steps, an HCV antibody test for screening and a nucleic acid amplification test (NAAT) for confirmation. However, the HCV core antigen (HCVcAg) detection assay is an alternative for one-step diagnosis. We aimed to evaluate the diagnostic performance of the Abbott ARCHITECT HCV Ag assay to detect active hepatitis C in serum/plasma in people living with HIV/AIDS (PLWHA), through a systematic review and meta-analysis. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched until 20 September 2022 (PROSPERO, CRD42022348351). We included studies evaluating Abbott ARCHITECT HCV Ag assay (index assay) versus NAATs (reference test) in PLWHA coinfected with HCV who did not receive antiviral treatment for HCV. Meta-analysis was performed with the MIDAS module using Stata and random-effects models. The QUADAS-2 tool evaluated the risk of bias. The bivariate analysis was conducted on 11 studies with 2,407 samples. Pooled sensitivity was 0.95 (95% CI = 0.92 to 0.97), specificity 0.97 (95% CI = 0.93 to 0.99), positive likelihood ratio 37.76 (95% CI = 12.84 to 111.02), and negative likelihood ratio 0.06 (95% CI = 0.04 to 0.09). The area under the curve was 0.97 (95% CI = 0.20 to 1.00). For low prevalence (≤5%), the posttest probability that an individual with a positive test was a true positive ranged from 4% to 67%, whereas, at high prevalence (≥10%), the posttest probability was between 81% and 87%, indicating that a confirmatory test should be necessary, particularly with prevalence values of ≤1%. Regardless of prevalence, the probability that an individual with a negative test was a false negative was close to zero, indicating that the individual was not infected with HCV. In conclusion, the accuracy of the Abbott ARCHITECT HCV Ag assay was very good for HCV screening in serum/plasma samples from PLWHA. The clinical utility to confirm HCV infection was acceptable in high-prevalence settings (≥10%) but poor in low-prevalence settings (≤1%). Furthermore, it was excellent in excluding active HCV infection.

Antibody levels to SARS-CoV-2 spike protein in mothers and children from delivery to six months later.

INTRODUCTION: Pregnant women are vulnerable to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. Neutralizing antibodies against the SARS-CoV-2 spike (S) protein protect from severe disease. This study analyzes the antibody titers to SARS-CoV-2 S protein in pregnant women and their newborns at delivery, and six months later. METHODS: We conducted a prospective study on pregnant women with confirmed SARS-CoV-2 infection and newborns. Antibody (IgG, IgM, and IgA) titers were determined using immunoassays in serum and milk samples. An angiotensin-converting enzyme 2 (ACE2) receptor-binding inhibition assay to the S protein was performed on the same serum and milk samples. RESULTS: At birth, antibodies to SARS-CoV-2 spike protein were detected in 81.9% of mothers' sera, 78.9% of cord blood samples, and 63.2% of milk samples. Symptomatic women had higher antibody titers (IgG, IgM, and IgA) than the asymptomatic ones (P < 0.05). At six months postpartum, IgG levels decreased drastically in children's serum (P < 0.001) but remained high in mothers' serum. Antibody titers correlated positively with its capacity to inhibit the ACE2-spike protein interaction at baseline in maternal sera (R2  = 0.203; P < 0.001), cord sera (R2  = 0.378; P < 0.001), and milk (R2  = 0.564; P < 0.001), and at six months in maternal sera (R2  = 0.600; P < 0.001). CONCLUSIONS: High antibody levels against SARS-CoV-2 spike protein were found in most pregnant women. Due to the efficient transfer of IgG to cord blood and high IgA titers in breast milk, neonates may be passively immunized to SARS-CoV-2 infection. Our findings could guide newborn management and maternal vaccination policies.

Neighborhood environmental factors linked to hospitalizations of older people for viral lower respiratory tract infections in Spain: a case-crossover study.

BACKGROUND: Lower respiratory tract viral infection (LRTI) is a significant cause of morbidity-mortality in older people worldwide. We analyzed the association between short-term exposure to environmental factors (climatic factors and outdoor air pollution) and hospital admissions with a viral LRTI diagnosis in older adults. METHODS: We conducted a bidirectional case-crossover study in 6367 patients over 65 years of age with viral LRTI and residential zip code in the Spanish Minimum Basic Data Set. Spain's State Meteorological Agency was the source of environmental data. Associations were assessed using conditional logistic regression. P-values were corrected for false discovery rate (q-values). RESULTS: Almost all were hospital emergency admissions (98.13%), 18.64% were admitted to the intensive care unit (ICU), and 7.44% died. The most frequent clinical discharge diagnosis was influenza (90.25%). LRTI hospital admissions were more frequent when there were lower values of temperature and O3 and higher values of relative humidity and NO2. The regression analysis adjusted by temperatures and relative humidity showed higher concentrations at the hospital admission for NO2 [compared to the lag time of 1-week (q-value< 0.001) and 2-weeks (q-value< 0.001)] and O3 [compared to the lag time of 3-days (q-value< 0.001), 1-week (q-value< 0.001), and 2-weeks (q-value< 0.001)] were related to a higher odds of hospital admissions due to viral LRTI. Moreover, higher concentrations of PM10 at the lag time of 1-week (q-value = 0.023) and 2-weeks (q-value = 0.002), and CO at the lag time of 3-days (q-value = 0.023), 1-week (q-value< 0.001) and 2-weeks (q-value< 0.001)], compared to the day of hospitalization, were related to a higher chances of hospital admissions with viral LRTI. CONCLUSION: Unfavorable environmental factors (low temperatures, high relative humidity, and high concentrations of NO2, O3, PM10, and CO) increased the odds of hospital admissions with viral LRTI among older people, indicating they are potentially vulnerable to these environmental factors.

Meta-analysis: diagnostic accuracy of hepatitis C core antigen detection during therapy with direct-acting antivirals.

BACKGROUND: Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) is monitored by assessing plasma HCV-RNA load. However, detection of HCV core antigen (HCVcAg) may be an alternative. AIM: To evaluate the diagnostic performance of the HCVcAg assay to monitor the efficacy of DAAs in HCV-infected patients METHODS: We performed searches in multiple electronic databases until 6 July 2022, of studies evaluating the HCVcAg detection in plasma or serum compared with the HCV-RNA test (gold standard). We calculated pooled measurement at 2 and 4 weeks of treatment, and at end-of-treatment (EOT), as well as sustained virological response (SVR; 12 weeks after EOT). RESULTS: We selected 16 studies from 2016 to 2022, with 3237 patients and 8958 samples. Overall, the diagnostic performance and clinical utility of the HCVcAg assay were poor at week 2 (sensitivity = 0.40, specificity = 0.96, positive likelihood ratio (PLR) = 9.16, negative likelihood ratio (NLR) = 0.63, and area under the summary receiver operating curve (SROC) = 0.57), fair at week 4 (sensitivity = 0.30, specificity = 0.90, PLR = 3.18, NLR = 0.77, and AUC = 0.79), acceptable at EOT (sensitivity = 0.40, specificity =0.98, PLR = 16.54, NLR = 0.62, and AUC = 0.97) and excellent for SVR (sensitivity = 0.94, specificity = 0.99, PLR = 107.54, NLR = 0.06, and AUC = 0.99). CONCLUSIONS: The HCVcAg assay may be helpful for monitoring the efficacy of HCV treatment with DAAs in HCV-infected patients at EOT and for documenting SVR, but not at weeks 2 and 4 of treatment due to poor diagnostic performance.

Environmental factors linked to hospital admissions in young children due to acute viral lower respiratory infections: A bidirectional case-crossover study.

OBJECTIVE: This study evaluated the association of the short-term exposure to environmental factors (relative humidity, temperature, NO2, SO2, O3, PM10, and CO) with hospital admissions due to acute viral lower respiratory infections (ALRI) in children under two years before the COVID-19 era. METHODS: We performed a bidirectional case-crossover study in 30,445 children with ALRI under two years of age in the Spanish Minimum Basic Data Set (MBDS) from 2013 to 2015. Environmental data were obtained from Spain's State Meteorological Agency (AEMET). The association was assessed by conditional logistic regression. RESULTS: Lower temperature one week before the day of the event (hospital admission) (q-value = 0.012) and higher relative humidity one week (q-value = 0.003) and two weeks (q-value<0.001) before the day of the event were related to a higher odds of hospital admissions. Higher NO2 levels two weeks before the event were associated with hospital admissions (q-value<0.001). Moreover, higher concentrations on the day of the event for SO2 (compared to lag time of 1-week (q-value = 0.026) and 2-weeks (q-value<0.001)), O3 (compared to lag time of 3-days (q-value<0.001), 1-week (q-value<0.001), and 2-weeks (q-value<0.001)), and PM10 (compared to lag time of 2-weeks (q-value<0.001)) were related to an increased odds of hospital admissions for viral ALRI. CONCLUSION: Short-term exposure to environmental factors (climatic conditions and ambient air contaminants) was linked to a higher likelihood of hospital admissions due to ALRI. Our findings emphasize the importance of monitoring environmental factors to assess the odds of ALRI hospital admissions and plan public health resources.

High Plasma sTNF-R1 Level Is Related to Loss of Natural HIV Control in Long-Term Elite Controllers.

Human immunodeficiency virus-1 (HIV-1) elite controllers are heterogeneous due to different immunovirological features. We aimed to identify plasma biomarkers associated with loss of spontaneous HIV-1 control in long-term elite controllers (HIV-LTECs). We performed a retrospective study in 60 HIV-LTECs [36 true-LTECs and 24 LTECs losing control (LTECs-LC)]. We selected a plasma sample from true-LTECs (towards the middle of the follow-up period) and two samples from LTECs-LC (one far from the loss of control and another close to loss of control). Plasma biomarkers were evaluated using multiplex immunoassays. The partial least squares-discriminant analysis provided the variable importance in projection (VIP), and the adjusted Generalized Linear Model provided the adjusted arithmetic mean ratio (aAMR). At the moment of the first LTECs-LC samples, the only plasma biomarker with a VIP≥1.5 was sTNF-R1, which showed higher values in LTECs-LC than true-LTECs [aAMR=1.62 (95%CI=1.20-2.19); p=0.001]. After a median of 3.9 (IQR=4.5) years of follow-up from the first sample, we also had access to a second plasma sample from 10 LTECs-LC patients. At the moment of this second LTECs-LC sample, the only plasma biomarker with VIP≥1.5 was also sTNF-R1, which showed higher values in LTECs-LC than true-LTECs [aAMR=1.93 (95%CI=1.41-2.65); p<0.001]. The difference between the first and second samples of LTECs-LC was significant (Δx= 6.58 (95%=0.3; 12.88); p=0.040). In conclusion, high plasma values of sTNF-R1 appear to discriminate HIV-LTECs that lose the natural control of HIV-1, helping to define a specific phenotype that may be useful for the clinical management of these patients.

Negative impact of HIV infection on broad-spectrum anti-HCV neutralizing antibody titers in HCV-infected patients with advanced HCV-related cirrhosis.

OBJECTIVES: The current study aimed to assess the impact of HIV on the production of anti-HCV antibodies in HCV-infected individuals with advanced HCV-related cirrhosis before and 36 weeks after the sustained virological response (SVR) induced by direct-acting antivirals (DAAs) therapy. METHODS: Prospective study on 62 patients (50 HIV/HCV-coinfected and 12 HCV-monoinfected). Plasma anti-E2 and HCV-nAbs were determined respectively by ELISA and microneutralization assays. RESULTS: At baseline, the HCV-group had higher anti-E2 levels against Gt1a (p = 0.012), Gt1b (p = 0.023), and Gt4a (p = 0.005) than the HIV/HCV-group. After SVR, anti-E2 titers against Gt1a (p < 0.001), Gt1b (p = 0.001), and Gt4a (p = 0.042) were also higher in the HCV-group than HIV/HCV-group. At 36 weeks post-SVR, plasma anti-E2 titers decreased between 1.3 and 1.9-fold in the HIV/HCV-group (p < 0.001) and between 1.5 and 1.8-fold in the HCV-group (p ≤ 0.001). At baseline, the HCV-group had higher titers of HCV-nAbs against Gt1a (p = 0.022), Gt1b (p = 0.002), Gt2a (p < 0.001), and Gt4a (p < 0.001) than the HIV/HCV-group. After SVR, HCV-nAbs titers against Gt1a (p = 0.014), Gt1b (p < 0.001), Gt2a (p = 0.002), and Gt4a (p = 0.004) were also higher in the HCV-group. At 36 weeks post-SVR, HCV-nAbs decreased between 2.6 and 4.1-fold in the HIV/HCV-group (p < 0.001) and between 1.9 and 4.0-fold in the HCV-group (p ≤ 0.001). CONCLUSIONS: HIV/HCV-coinfected patients produced lower levels of broad-spectrum anti-HCV antibodies than HCV-monoinfected patients.

Baseline and time-updated factors in preclinical development of anionic dendrimers as successful anti-HIV-1 vaginal microbicides.

Although a wide variety of topical microbicides provide promising in vitro and in vivo efficacy, most of them failed to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1) in human clinical trials. In vitro, ex vivo, and in vivo models must be optimized, considering the knowledge acquired from unsuccessful and successful clinical trials to improve the current gaps and the preclinical development protocols. To date, dendrimers are the only nanotool that has advanced to human clinical trials as topical microbicides to prevent HIV-1 transmission. This fact demonstrates the importance and the potential of these molecules as microbicides. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV-1 that disturb HIV-1 entry. Herein, the most significant advancements in topical microbicide development, trying to mimic the real-life conditions as closely as possible, are discussed. This review also provides the preclinical assays that anionic dendrimers have passed as microbicides because they can improve current antiviral treatments' efficacy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients.

Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFß) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways ("cytokine-cytokine receptor interaction", "viral protein interaction with cytokine and cytokine receptor", "chemokine signaling pathway", and "hepatitis C"). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.

BMS Derivatives C7-Linked to ß-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides.

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (ß-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4th generation, are reported here for the first time.

Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis.

Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.

Hepatitis C virus vaccine design: focus on the humoral immune response.

Despite the recent development of safe and highly effective direct-acting antivirals, hepatitis C virus (HCV) infection remains a significant health problem. In 2016, the World Health Organization set out to reduce the rate of new HCV infections by 90% by 2030. Still, global control of the virus does not seem to be achievable in the absence of an effective vaccine. Current approaches to the development of a vaccine against HCV include the production of recombinant proteins, synthetic peptides, DNA vaccines, virus-like particles, and viral vectors expressing various antigens. In this review, we focus on the development of vaccines targeting the humoral immune response against HCV based on the cumulative evidence supporting the important role of neutralizing antibodies in protection against HCV infection. The main targets of HCV-specific neutralizing antibodies are the glycoproteins E1 and E2. Recent advances in the knowledge of HCV glycoprotein structure and their epitopes, as well as the possibility of getting detailed information on the human antibody repertoire generated by the infection, will allow rational structure-based antigen design to target specific germline antibodies. Although obtaining a vaccine capable of inducing sterilizing immunity will be a difficult task, a vaccine that prevents chronic hepatitis C infections, a more realistic goal in the short term, would have a considerable health impact.

Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants.

Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.

Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria.

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.

Drug discovery technologies: Caenorhabditis elegans as a model for anthelmintic therapeutics.

Helminthiasis is one of the gravest problems worldwide. There is a growing concern on less available anthelmintics and the emergence of resistance creating a major threat to human and livestock health resources. Novel and broad-spectrum anthelmintics are urgently needed. The free-living nematode Caenorhabditis elegans could address this issue through automated high-throughput technologies for the screening of large chemical libraries. This review discusses the strong advantages and limitations for using C elegans as a screening method for anthelmintic drug discovery. C elegans is the best model available for the validation of novel effective drugs in treating most, if not all, helminth infections, and for the elucidation the mode of action of anthelmintic candidates. This review also focuses on available technologies in the discovery of anthelmintics published over the last 15 years with particular attention to high-throughput technologies over conventional screens. On the other hand, this review highlights how combinatorial and nanomedicine strategies could prolong the use of anthelmintics and control resistance problems.