bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Activity of Proteasome Inhibitors in Herpes Simplex Virus-1 Infection: Role of Nuclear Factor-κB
Authors: Frazia Simone La , Amici Carla , Santoro M Gabriella 
Published: April 2022

Background Herpes simplex virus type 1 (HSV-1) is a potent inducer of nuclear factor-κB (NF-κB), a cellular transcription factor with a crucial role in promoting inflammation and controlling cell proliferation and survival. Objectives On the basis of the recent demonstration that HSV-1-induced NF-κB is actively recruited to κB-binding sites in the HSV-1 infected-cell protein 0 (ICP0) promoter enhancing viral transcription and replication, we investigated the effect of proteasome inhibitors MG132, MG115 and epoxomicin, which block NF-κB function by preventing the degradation of the inhibitory proteins IκBα, on HSV-1-induced NF-κB activation and viral replication. Methods Antiviral activity of proteasome inhibitors was analysed in HSV-1-infected HEp2 cells by determining infective virus titres by CPE50%, viral RNA synthesis by RT-PCR, and viral protein synthesis by immunoblot analysis or immunofluorescence. ICP0 transcription was studied in transient transfection experiments using the ICP0 promoter-luciferase IE1-Luc construct. IκBα degradation and NF-κB activity were determined by immunoblot analysis and EMSA, respectively. Results Proteasome inhibitors were found to prevent HSV-1-induced NF-κB activation in the early phase of infection. Block of virus-induced NF-κB activation resulted in inhibiting HSV-1 ICP0 gene expression, in decreasing the level of immediate-early and late viral proteins, and ultimately in greatly suppressing viral replication. The antiviral effect was lost if treatment was started after NF-κB activation, and appeared to be independent of the HSV-1-induced activation of the JNK pathway. Conclusions Proteasome inhibitors possess NF-κB-dependent antiherpetic activity. The results described further identify the IKK/NF-κB pathway as a suitable target for novel antiherpetic drugs.
Limited Impact of Immunosuppression and Haart on the Incidence of Cervical Squamous Intraepithelial Lesions in HIV-Positive Women
Authors: Heard Isabelle , Potard Valérie , Costagliola Dominique 
Published: April 2022

Background Although highly active antiretroviral therapy (HAART) has lowered the incidence of various opportunistic diseases, its impact on cervical squamous intraepithelial lesions (SILs) is unclear. Our objective was to compare the incidence of SILs in HIV-infected women receiving HAART versus those not receiving HAART and to determine the role of risk factors including immunosuppression in the pathogenesis of SIL. Methods A total of 298 HIV-infected women with normal Papanicolaou (Pap) smear and normal colposcopic findings at enrollment were followed-up until incident SIL or last follow-up visit. Cox regression modelling was used to assess risks factors for incident SIL. Results Eighty-eight women developed SILs, including 75 low-grade lesions, during a median follow-up of 28 months (16–52; incidence of 8.7 cases per 100 person-years). No invasive cervical cancers were identified. Incidence decreased from 10.7 to 6.5 per 100 person-years in non-receiving versus receiving HAART women (relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.4–1.2, P=0.15, from the adjusted Cox model). Incident SIL was not associated to low CD4+ T-cell count ( P=0.54). In multivariate analysis, the only significant risk factor for incident lesion was the age between 30–39 compared with over 40 (RR: 3.5; 95% CI: 1.4–8.9; P=0.02). Conclusion No impact in the development of SIL was evidenced for CD4+ T-cell counts, but we cannot exclude a modest impact of HAART. All HIV-positive women should be offered to participate in cervical cancer screening programmes whether or not they receive effective antiretroviral therapy.
Inhibition of Simian Virus 40 Large T Antigen Helicase Activity by Fluoroquinolones
Authors: Ali Syed Hamid , Chandraker Anil , DeCaprio James A 
Published: April 2022

Background Fluoroquinolones represent a potent group of antibiotics that inhibit bacterial DNA replication by targeting the essential bacterial enzymes gyrase and topoisomerase IV. Inhibition of gyrase activity by quinolones involves the interaction of these drugs with the helicase component of bacterial gyrase. DNA tumour viruses also encode helicases that are essential for their DNA replication in the host. Methods In this study we have evaluated the effect of fluoroquinolones on viral DNA replication using the DNA tumour virus Simian virus 40 (SV40) as our model. Four different fluoroquinolones, namely, levofloxacin, trovafloxacin, ciprofloxacin and ofloxacin, were tested for their ability to inhibit viral DNA replication. Results We show here that all four quinolones tested were effective in the inhibition of SV40 plaque formation and DNA replication in CV1-P cells. In addition, we found that each of these quinolones was inhibitory to the helicase activity of SV40 large tumour antigen. Conclusions Fluoroquinolones and their derivates may therefore be useful in the treatment and/or prevention of infection by SV40-homologous human DNA viruses that encode helicase activity for their survival.
Liver Triglyceride Content in HIV-1-Infected Patients on Combination Antiretroviral Therapy Studied with 1H-MR Spectroscopy
Authors: Moreno-Torres Angel , Domingo Pere , Pujol Jesus , Blanco-Vaca Francisco , Arroyo Juan Antonio , Sambeat M Antonia 
Published: April 2022

Objective To carry out an exploratory evaluation of liver triglyceride content in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) using proton magnetic resonance spectroscopy and to study how both the treatment itself and the biochemical and physiological variables in which the treatment causes alterations are related to liver fat content. Methods Intracellular hepatic triglyceride content was determined in 29 HIV-1-infected patients on their first HAART regime by means of localized water-unsuppressed single voxel proton spectra. Other measurements were body mass index, waist-to-hip ratio, lipodystrophy assessment and a detailed blood biochemical analysis. The relationship between intracellular hepatic triglycerides and relevant descriptive, treatment and biochemical variables was studied by correlation and regression analysis. Results Intrahepatic triglycerides were detected in 58.6% of the patients and 13.8% showed a triglyceride content compatible with liver steatosis. Many variables (body mass index, waist-to-hip ratio, cumulative exposure to PIs, lactate, insulin, insulin resistance measured by the homeostasis model assessment method [HOMA-R index], pH, total triglycerides, high density lipoprotein cholesterol and very low density lipoprotein [VLDL] cholesterol) correlated individually with the amount of triglycerides. Stepwise multiple regression analysis showed that the combination of insulin or HOMA-R index and VLDL cholesterol accounted for up to 50.2% of the triglyceride liver variance. A positive relationship was found between the concomitant presence of the metabolic syndrome components (insulin resistance, dyslipidaemia and central obesity) and intrahepatic triglyceride content. Conclusions The study showed that intrahepatic triglyceride deposit appears to be a frequent feature of HIV-1-infected patients receiving HAART. A coherent multifactorial combination of biochemical and physiological factors associated with the deposit suggested that cumulative exposure to PIs might be a possible trigger event.
Altered Heterochromatin Organization after Perinatal Exposure to Zidovudine
Authors: Senda Sho , Blanche Stéphane , Costagliola Dominique , Cibert Christian , Nigon Fabienne , Firtion Ghilaine , Floch Corinne , Parat Sophie , Viegas-Péquignot Evani 
Published: April 2022

Background Zidovudine (3’-azido-3’-deoxythymidine, AZT), administered to pregnant women alone or in combination with other antiretroviral drugs, greatly reduces the mother-to-child transmission of HIV-1. The potential genotoxicity of these molecules is underestimated and wide-ranging evaluation of its biological and clinical consequences is required. Methods We investigated the nuclear organization of constitutive heterochromatin, a major domain participating in epigenetic regulation, in uninfected infants born to HIV-1-infected mothers treated with zidovudine and/or other nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy. We studied the organization of chromosome 1 heterochromatin (1q12) in peripheral leukocytes of 25 HIV-1-uninfected children (newborn to 9 years old): children born to HIV-1-infected mothers exposed to zidovudine and/or other NRTIs ( n=15), children born to HIV-1-infected mothers not exposed to any NRTIs ( n=6) and children born to HIV-1-uninfected mothers ( n=4). Results Results differed significantly between NRTI-exposed and -unexposed children. By contrast, there was no difference between NRTI-unexposed children born to HIV-1-infected mothers and children born to HIV-uninfected mothers. The anomaly persisted in lymphocytes cultured for 48 h. There was no evidence of abnormal DNA methylation, a major feature of constitutive heterochromatin and associated with the loss of its structure. In a complementary sample of children, analysis of chromosome 11 and 16 heterochromatin suggests that the defect affects most of the other heterochromatic sites of the human genome. The heterochromatin defect persists long after the end of the exposure and appears in leukocytes of both myeloid and lymphoid lineages, suggesting that haematopoietic stem cells are affected.
The V118I Mutation as a Marker of Advanced HIV Infection and Disease Progression
Authors: Zaccarelli Mauro , Tozzi Valerio , Lorenzini Patrizia , Forbici Federica , Narciso Pasquale , Ceccherini-Silberstein Francesca , Trotta Maria Paola , Bertoli Ada , Liuzzi Giuseppina , Marconi Patrizia , Mosti Silvia , Perno Carlo Federico , Antinori Andrea 
Published: April 2022

Background The V118I mutation is included in the nucleoside analogue mutations (NAMs) set. It contributes to thymidine-analogue resistance and, consequently, to resistance to the whole nucleoside reverse transcriptase inhibitor (NRTI) class. We focused on the V118I mutation in order to evaluate factors associated with its detection and its relationship with HIV progression. Methods Clinical and laboratory data at genotypic resistance test (GRT) of highly active antiretroviral therapy-failing patients were collected and their association with the V118I mutation was analysed. Patients were also followed over time to determine factors related to progression to a new AIDS-related event or death. Results Of the 792 patients included, 114 (14.4%) carried the V118I mutation. In univariate analysis, the V118I mutation was significantly associated with a higher HIV RNA level, lower CD4+ T-cell count, Centers for Disease Control and Prevention (CDC) stage C, higher number of pre-GRT regimens and class-wide resistance (CWR) to NRTIs, protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Higher numbers of pre-GRT regimens and NRTI CWR were also associated in the multivariable analysis. Within the post-GRT observation period of up to 6 years (median: 72 months; interquartile range: 33–109) 107 events (58 new AIDS-related diseases and 49 deaths) were observed. Using the Cox proportional hazard model and the major clinical, behavioural and laboratory data, the V118I mutation was found to be associated with the endpoint (hazard ratio: 1.93, 95% confidence interval: 1.06–3.50; P=0.031). Other factors associated with disease progression were CDC stage C and lower CD4+ T-cell count at GRT. Conclusions The analysis of our observational database suggests that the onset of the V118I mutation after treatment failure is unfavourable for the patient and can be considered a strong marker of disease progression.
Long-Term Foscarnet Therapy Remodels Thymidine Analogue Mutations and Alters Resistance to Zidovudine and Lamivudine in HIV-1
Authors: Mathiesen Sofie , Dam Elisabeth , Roge Birgit , Joergensen Louise Bruun , Laursen Alex Lund , Gerstoft Jan , Clavel Francois 
Published: April 2022

Objective To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations. Methods Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4–3. Reversion of single mutations was performed in a patient-derived recombinant clone. Results Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received >12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3–6-fold resistance to PFA, a 2–20-fold decrease in resistance to zidovudine compared to baseline, and 14–39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of ≥3 mutations (K70G+K219R+L228R±V75T) induced PFA resistance and decreased zidovudine resistance 3–13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G→R and K219R→E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance. Conclusions In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.
The Magnitude of Week 4 HCV RNA Decay on Pegylated Interferon/Ribavirin Accurately Predicts Virological Failure in Patients with Genotype 1
Authors: Bárcena Rafael , Moreno Ana , Del Campo Santos , Muriel Alfonso , Mateos María L , Garrido Elena , García Miguel , Quereda Carmen , Moreno Santiago , Moreno Alberto 
Published: April 2022

Background Current stopping rules during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment rely on week 12 HCV RNA response, but earlier identification of non-responders offers clinical and economic advantages. Aims and Methods To evaluate, among 129 HCV-genotype-1-infected, treatment-naive patients receiving peg-IFN/RBV, the feasibility of predicting treatment failure using receiver operating characteristics (ROC) curves after measuring week 4 HCV RNA decreases, and to assess baseline predictors of not achieving sustained virological response (SVR). Results Peg-IFN-α2b was used in 84.5% of patients. Fifty-three (41%) reached SVR. The best cutoff value of HCV RNA decrease at week 4 to predict non-SVR corresponded to 1 log10 IU/ml: sensitivity and negative predictive value: 100%; specificity: 64%; positive predictive value: 66%; ROC curve area: 0·91 (95% confidence interval [CI]: 0·86–0·96). By applying this threshold, treatment could have been discontinued at week 4 in 64% of virological non-responders (49/76). By univariate analysis, baseline HCV RNA >800,000 IU/ml ( P=0.029), older age ( P=0.011), and higher aspartate aminotransferase (AST) levels ( P=0.005) or AST/alanine aminotransferase ratio values ( P=0.04) were associated with failure. After multivariate analysis, only baseline HCV RNA >800,000 IU/ml (odds ratio [OR]: 2.12; 95% CI: 1.005–4.488; P=0.048) and higher AST levels (OR: 1.01; 95% CI: 1.003–1.024; P=0.011) remained statistically significant. Conclusions The lack of ≥1 log10 IU/ml decrease in baseline HCV RNA at week 4 was 100% predictive of treatment failure, independently associated with HCV RNA >800,000 IU/ml and higher AST levels.
First-line Highly Active Antiretroviral Regimens in 2001–2002 in the French Hospital Database on HIV: Combination Prescribed and Biological Outcomes
Authors: Potard Valérie , Rey David , Mokhtari Saadia , Frixon-Marin Véronique , Pradier Christian , Rozenbaum Willy , Brun-Vezinet Françoise , Costagliola Dominique ,   the French Hospital Database on HIV, ANRS C04
Published: April 2022

Introduction We compared biological outcomes in anti-retroviral-naive patients with viral load (VL) >5,000 copies/ml starting combivir-based, three-drug highly active antiretroviral therapy regimens in 2001–2002 according to the third component, namely abacavir (ABC), nelfinavir (NFV), indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), nevirapine (NVP) or efavirenz (EFV). Methods We evaluated virological response (HIV RNA <500 copies/ml) and immunological response (increase of ≥50 CD4+ T-cells/u, l) separately in patients with baseline VL <100,000 copies/ml ( n=992) and ≥100,000 copies/ml ( n=1,048). Hazard ratios (HR) were calculated with Cox models stratified for quintiles of propensity scores, estimated by multinomial regression from baseline characteristics. Results Median follow up was 19 months. EFV had better virological efficacy than NFV and IDV/r among patients with baseline VL <100,000 copies/ml, with respective HRs of 0.71 and 0.72, compared with 0.81 for NVP, 0.89 for ABC and 0.99 for LPV/r. The immunological efficacy of EFV was lower than that of LPV/r (1.37) and similar to that of NFV (0.96), IDV/r (0.81), NVP (1.08) and ABC (1.04). Among patients with baseline VL ≥100,000 copies/ml, the virological efficacy of EFV was similar to that of NVP (0.90) and LPV/r (0.97) and better than that of NFV (0.62), ABC (0.75) and IDV/r (0.78). The immunological results found in these patients were similar to those observed in patients with baseline VL <100,000 copies/ml. Conclusions For first-line therapy, in this observational setting, EFV, LPV/r and NVP, when added to the combivir backbone, were more likely to drive viral load <500 copies/ml. LPV/r showed the best immunological effectiveness.
Plasma Concentrations of the HIV-Protease Inhibitor Lopinavir are Suboptimal in Children Aged 2 Years and Below
Authors: Verweel Gwenda , Burger David M , Sheehan Nancy L , Bergshoeff Alina S , Warris Adilia , Van Der Knaap Linda C , Driessen Gertjan , de Groot Ronald , Hartwig Nico G 
Published: April 2022

Background Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective. Methods HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was <1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48. Results A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4–13.2) years. Mean (±SD) AUC0–12h, Cmax and Cmin of LPV were 75.3 (±33.7) mg/l.h, 9.33 (±3.27) mg/l and 3.68 (±2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children <2 years had inadequate Cmin compared with children >2 years. Dose increase to ±300/75 mg/m2 LPV/r led to Cmin >1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients. Conclusions Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children <2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.
Some HIV Antiretrovirals Increase Oxidative Stress and Alter Chemokine, Cytokine or Adiponectin Production in Human Adipocytes and Macrophages
Authors: Lagathu Claire , Eustace Brenda , Prot Matthieu , Frantz Dan , Gu Yong , Bastard Jean-Philippe , Maachi Mustapha , Azoulay Stephane , Briggs Michael , Caron Martine , Capeau Jacqueline 
Published: April 2022

Objectives Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients’ insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals. Methods Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24–48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays. Results In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1α and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1β and tumour necrosis factor-α. Conclusions Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.