bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mannose-Binding Lectin in Susceptibility and Progression of HIV-1 Infection in Children
Authors: Dzwonek Agnieszka , Novelli Vas , Bajaj-Elliott Mona , Turner Malcolm , Clapson Margaret , Klein Nigel 
Published: April 2022

Background Mannose-binding lectin (MBL; encoded by MBL-2) is a circulating pattern-recognition molecule that recognizes microbial carbohydrate motifs, leading to complement activation and cell lysis. Mutations in the MBL-2 promoter and of the MBL-2 gene exon 1 result in reduced protein levels and increased susceptibility to infection. We have investigated the effect of MBL-2 polymorphisms on susceptibility and progression of HIV-1 infection in children. Patients and methods One-hundred and twenty-eight children, aged 2–16 years were recruited. MBL-2 genotypes were determined by PCR and heteroduplex analyses. Serum MBL levels were measured by ELISA. Comparison of genotypes (A=wild type, 0=variant alleles) and protein levels between groups was performed using χ2, Mann–Whitney U or Kruskal–Wallis tests. Results Children were classified according to the Centers for Disease Control and Prevention clinical classification: A, B or C (mildly symptomatic [ n=39], moderately symptomatic [ n=58] or severely symptomatic AIDS [ n=31]) or immune category 1 ( n=77), 2 ( n=46) or 3 ( n=5). Analysis of MBL-2 genotypes with respect to clinical classification yielded minimal differences. However, patients in immunological categories 2 and 3 (<25% CD4+ T cells) were more likely to have MBL-2 variant alleles ( P=0.01). We further explored MBL status with respect to disease progression. Only 1/10 long-term non-progressors (LTNPs) had an MBL-2 mutation (A/D) with a corresponding protein level of 611 ng/ml. Conclusions MBL deficiency was more frequent in patients with severe disease as assessed by CD4+ T-cell status. MBL-2 variants may be less frequent in children classified as LTNPs. MBL analysis could be useful in identifying children with slow disease progression and, consequently, may not require immediate antiretroviral treatement.
Foscarnet Salvage Therapy for Patients with Late-Stage HIV Disease and Multiple Drug Resistance
Authors: Canestri Ana , Ghosn Jade , Wirden Marc , Marguet Françoise , Ktorza Nadine , Boubezari Imane , Dominguez Stéphanie , Bossi Philippe , Caumes Eric , Calvez Vincent , Katlama Christine 
Published: April 2022

Objective To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. Methods Three drugs experienced patients with plasma viral load (pVL) >50,000 copies/ml and CD4+ T-cell counts <100/mm3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log10 decrease in pVL at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6. Results Eleven patients were enrolled with a median baseline pVL at 5.16 log10 copies/ml, median CD4+ T-cell count at 10/mm3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intent-to-treat analysis, the median change in pVL from baseline was -1.99 log10 copies/ml at W2 and -1.79 log10 copies/ml at W6. Eight out of eleven patients had a fall in pVL of at least 1 log10 at W6, and six started maintenance therapy. The median fall in pVL after 12 weeks of maintenance therapy was -0.85 log10 copies/ml in the four patients who reached W12, and the median increase of CD4+ T-cell count was 60/mm3. Conclusion In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.
Does Haart Improve Renal Function? An Association between Serum Cystatin C Concentration, HIV Viral Load and Haart Duration
Authors: Jaroszewicz Jerzy , Wiercinska-Drapalo Alicja , Lapinski Tadeusz W , Prokopowicz Danuta , Rogalska Magdalena , Parfieniuk Anna 
Published: April 2022

Aim The prevalence of renal disease in human HIV-infected individuals varies between 2% and 10%. Many reports have demonstrated the beneficial effect of anti-retroviral (ARV) therapy on slowing the progression of renal diseases. The aim of our cross-sectional study was to determine serum cystatin C concentration in different stages of HIV infection and the relationship between cystatin C concentration and ARV treatment. Methods Cystatin C concentration was measured in the sera of 77 HIV-1-infected individuals and 18 HIV-seronegative volunteers. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study formula. Results HIV infection resulted in a significant increase in serum cystatin C concentration compared with healthy individuals (933.4±32.1 vs 621.1 ±56.8 ng/ml, P<0.001). There were no significant differences in urea, creatinine and GFR between those groups. On multivariate analyses serum cystatin C was independently associated with highly active antiretroviral therapy (HAART) duration (β=-0.34, P=0.04) and HIV viral load (β=0.33, P=0.04), whereas there were no significant relationships with age, body mass index, HIV duration, CD4+ and CD8+ T-cell counts and serum high sensitivity C-reactive protein concentration. Conclusions Our initial observations indicate that serum cystatin C, which may reflect mild renal dysfunction, is increased during HIV-infection and is associated with HIV viral load. Long-lasting HAART seems to decrease cystatin C concentration, thus potentially improves renal function.
Amdoxovir versus Placebo with Enfuvirtide plus Optimized Background Therapy for HIV-1-Infected Subjects Failing Current Therapy (Aactg A5118)
Authors: Gripshover Barbara M , Ribaudo Heather , Santana Jorge , Gerber John G , Campbell Thomas B , Hogg Evelyn , Jarocki Bernadette , Hammer Scott M , Kuritzkes Daniel R 
Published: April 2022

Background Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses. Methods ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade ≥3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks. Results Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI=-2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI=-1.1, -0.1) in the placebo arm ( P=0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI=1, 115) in the DAPD arm and 60 (95% CI=1, 101) in the placebo arm ( P=0.45). Time to first serious AE did not differ between arms ( P=0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities. Conclusions Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.
Declining Prevalence of HIV-Infected Individuals at Risk of Transmitting Drug-Resistant HIV in Denmark during 1997–2004
Authors: Lohse Nicolai , Obel Niels , Kronborg Gitte , Jørgensen Louise Bruun , Pedersen Court , Larsen Carsten Schade , Kvinesdal Birgit , Sørensen Henrik Toft , Gerstoft Jan 
Published: April 2022

Background Transmission of drug-resistant HIV is a potential threat to the substantial clinical benefit of highly active antiretroviral therapy (HAART). To explore the background for the low rates of drug resistance transmission (2–5%) in our population, we estimated acquisition of HIV drug resistance and examined temporal trends in the prevalence of patients at risk of transmitting drug-resistant HIV. Methods The study population included all 4,025 patients from The Danish HIV Cohort Study seen during the period 1995–2004. Virological failure to a given drug class was defined as a viral load (VL) >1,000 copies/ml for 120 days while on a HAART regimen including that drug class. In addition, receiving nucleoside reverse transcriptase inhibitors (NRTIs) for 180 days before HAART counted as NRTI failure irrespective of VL. Having experienced failure was considered a proxy for harbouring drug-resistant virus in subsequent observation time. Patients with a current VL >1,000 copies/ml were considered at risk of transmitting HIV. Results We found a decrease from 1997 to 2004 in the prevalence of potential transmitters of drug-resistant HIV. The number of these patients with previous NRTI failure decreased from 429 (24% of all patients) in 1998 to 213 (8.0% of all patients) in 2004. Previous protease inhibitor (PI) failure peaked at 279 (14%) in 1999, declining to 142 (5.3%) in 2004. Previous NNRTI failure peaked at 121 patients (4.7%) in 2002, and occurred in 113 patients (4.2%) in 2004. Of all 686 potential transmitters in 2004, 31% had previously experienced NRTI failure, 21% PI failure, and 16% non-NRTI failure. Conclusion In the population of HIV-infected individuals in Denmark with complete follow-up, the number at risk of transmitting drug-resistant virus declined over time.
Metabolic and Mitochondrial Effects of Switching Antiretroviral-Experienced Patients to Enfuvirtide, Tenofovir and Saquinavir/Ritonavir
Authors: Miró Òscar , Garrabou Glòria , López Sònia , Deig Elisabeth , Vidal Immaculada , Infante Anna B , Cardellach Francesc , Casademont Jordi , Pedrol Enric 
Published: April 2022

Objective Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity. Patients and Methods Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART. Results Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL ( P=NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly ( P<0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients ( P<0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P<0.05), complex III activity (127%, P<0.05), complex IV activity (86%, P=0.37) and oxygen consumption (194%, P<0.05). Conclusion Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.
Virological Response and Incidence of Adefovir Resistance in Lamivudine-Resistant Patients Treated with Adefovir Dipivoxil
Authors: Chen Chien-Hung , Wang Jing-Houng , Lee Chuan-Mo , Hung Chao-Hung , Hu Tsung-Hui , Wang Jyh-Chwan , Lu Sheng-Nan , Changchien Chi-Sin 
Published: April 2022

Background and aims The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients. Patients and methods Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance. Results IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86–0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12–25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance. Conclusion Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.
A Virosomal Immunization Strategy against Cervical Cancer and Pre-Malignant Cervical Disease
Authors: Bungener Laura , de Mare Arjan , de Vries-Idema Jacqueline , Sehr Peter , van der Zee Ate , Wilschut Jan , Daemen Toos 
Published: April 2022

In this study, we demonstrate that fusion-active virosomes, containing recombinant human papillomavirus type 16 (HPV16) E7 protein antigen, are capable of inducing a robust class I MHC-restricted cytotoxic T-lymphocyte (CTL) response against HPV-transformed tumour cells in a murine model system. Virosomes are reconstituted viral envelopes, which do not contain the genetic material of the native virus. During the reconstitution process, protein antigens can be encapsulated within the virosomes. In the present study, we used virosomes derived from influenza virus. These virosomes retain the cell binding and membrane fusion characteristics of native influenza virus, and have the capacity to deliver encapsulated antigens to the cytosol of antigen-presenting cells through fusion from within acidic endosomes. After immunization of mice with virosomes containing encapsulated HPV16 E7 protein, the animals developed a strong E7–specific CTL response as assessed by 51Cr release measurements and MHC tetramer staining of spleen cells. Immunization with E7–containing virosomes also resulted in E7-specific antibody responses. In tumour challenge experiments, immunization of mice with E7-containing virosomes prevented tumour outgrowth in >70% of the animals. Thus, influenza-derived virosomes with encapsulated HPV E7 protein antigen act as an excellent vaccine delivery system for induction of cellular immunity against HPV-transformed cells and represent a promising immunotherapeutic vaccine for the treatment of (precursor lesions of) cervical cancer.
Cerebrospinal Fluid Viral Loads Reach Less than 2 Copies/ML in HIV-1-Infected Patients with Effective Antiretroviral Therapy
Authors: Yilmaz Aylin , Svennerholm Bo , Hagberg Lars , Gisslén Magnus 
Published: April 2022

Background A low-grade persisting viraemia despite long-term treatment with highly active antiretroviral therapy (HAART) has previously been demonstrated in HIV-1-infected patients. Whether ongoing viral replication also could be detected in cerebrospinal fluid (CSF) in those circumstances has not been studied before. Methods Paired CSF and blood samples from 13 neurologically asymptomatic HIV-1-infected patients on stable HAART were analysed regarding HIV-1 RNA, by using a PCR assay with a detection limit of 2 copies/ml. Results All 13 patients had HIV-1 RNA <2 copies/ml in CSF, compared with 8/13 in plasma. Conclusion We could not demonstrate any persistent viral replication in the CSF of neurologically asymptomatic HIV-1-infected patients on effective HAART, rendering it unlikely that CSF acts as a viral reservoir in this category of patients.
Compensatory Mutations at the HIV Cleavage Sites P7/P1 and P1/P6-Gag in Therapy-Naive and Therapy-Experienced Patients
Authors: Verheyen Jens , Litau Elena , Sing Tobias , Däumer Martin , Balduin Melanie , Oette Mark , Fätkenheuer Gerd , Rockstroh Jürgen K , Schuldenzucker Ulrike , Hoffmann Daniel , Pfister Herbert , Kaiser Rolf 
Published: April 2022

Background Mutations in the genome of HIV conferring drug resistance are a major reason for the failure of antiretroviral therapy, but they often compromise viral fitness. Protease (PR) cleavage site (CS) mutations could compensate for impaired replication capacity of drug-resistant viruses. Patients and methods We analysed the cleavage sites p1/p7 and p1/p6-gag of 500 HIV-1 subtype B infected patients. The collective consists of 275 therapy-naive and 225 therapy-experienced patients with at least one primary PR mutation, from whom eight underwent therapy-interruption in different clinical settings. Results Multiple mutations within the CS p7/p1 and p1/p6-gag accumulated in therapy-experienced isolates (p7/p1: A431V-K436R-I437V and p1/p6-gag: L449F/V-P452S-P453L/A). Further rare CS mutations were totally absent in therapy-naive viruses. Sixty percent of all therapy-experienced viruses exhibited at least one therapy-associated CS mutation, but so did 10% of therapy-naive viruses. The analysis of CS and PR mutations in therapy-experienced viruses revealed several positive correlations - A431V with L24I-M46I/L-I54V-V82A; I437V with I54V-V82F/T/S; L449V with I54M/L/S/T/A; and L449F/R452S/P453L: with D30N-I84V - whereas P453L and V82A were negatively correlated. Mutagenetic trees constructed form this cross-sectional data showed an ordered accumulation of the most prominent CS mutations along two pathways - L90M-I84V- P453L and I54-V82– A431V followed by either M46L or L24I. Furthermore, eight viruses with at least one therapy-associated mutation at each CS displayed an outstanding maintenance of major PR mutations during therapy interruption. Conclusions These findings emphasize the relevance of CS mutations in the evolution of HIV resistance to PR inhibitors. Therefore, therapy-associated CS mutations should be considered in HIV resistance tests to estimate viral fitness in different clinical settings.
A Prospective Clinical and Pathological Examination of Injection Site Reactions with the HIV-1 Fusion Inhibitor Enfuvirtide
Authors: Myers Sarah A , Selim Angelica A , McDaniel Margaret A , Hall Russell , Zhang Ying , Bartlett John A , True Andrea L 
Published: April 2022

Objective Antiretroviral regimens containing the fusion inhibitor enfuvirtide (ENF) are associated with sustained viral suppression and immunological benefit. However, local injection site reactions (ISR) occur in the majority of patients. The aim of this study was to determine the pathogenesis of ISRs. Methods Injection sites were evaluated prospectively from 30 min up to 15–30 days post-injection in ENF-experienced (Cohort I) and ENF-naive patients (Cohort II) during the first 2 weeks of therapy. Four to five injections were given in rotating abdominal sites by a nurse using a standardized technique and were rigorously evaluated. Results Reactions were observed in 80–100% of patients; the majority of the reactions were mild to moderate, generally appeared within 24–48 h post-injection, and pain, induration and erythema were the most common clinical signs. Whereas most patients experienced ISRs, the overall prevalence in Cohort II was low (35% maximum). Punch biopsies of injection sites in Cohort I consisted primarily of mixed lymphocytic infiltrates with eosinophils and neutrophils. Injection vehicle (ENF buffer minus ENF) and reduced volume (2x0.5 ml ENF [45 mg] versus 1.0 ml [90 mg] ENF) were investigated in Cohort II. Fewer reactions appeared with vehicle and pain was absent with the smaller injection volume. Pathology was indistinguishable between ENF, vehicle and normal tissue in Cohort II patients. Conclusion These results suggest that injection technique, injection volume and peptide may influence ISR to ENF.
Indomethacin Has a Potent Antiviral Activity against Sars Coronavirus
Authors: Amici Carla , Caro Antonino Di , Ciucci Alessandra , Chiappa Lucia , Castilletti Concetta , Martella Vito , Decaro Nicola , Buonavoglia Canio , Capobianchi Maria R , Santoro M Gabriella 
Published: April 2022

Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections. Objectives Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication. Methods Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methio-nine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO). Results Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs. Conclusions The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.