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1.
The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon.
Krarup, AR, Abdel-Mohsen, M, Schleimann, MH, Vibholm, L, Engen, PA, Dige, A, Wittig, B, Schmidt, M, Green, SJ, Naqib, A, et al
Mucosal immunology. 2018;(2):449-461
Abstract
Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.
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Similar long-term efficacy of dual therapy containing raltegravir and a boosted protease inhibitor versus standard triple therapies in pretreated HIV-1-infected patients in a retrospective, real-life cohort of 14 years.
Krznaric, I, Bickel, M, Carganico, A, De Leuw, P, Haberl, A, Knecht, G, Koegl, C, Lauscher, P, Schüttfort, G, Stephan, C, et al
HIV medicine. 2018;(9):662-667
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Abstract
OBJECTIVES Raltegravir is used in many antiretroviral combinations, but its use in treatment-experienced patients without knowledge of baseline resistance is discussed controversially as a number of comparative studies have shown a higher rate of virological failure. However, it has been used frequently for the management of treatment failure, as it was the first integrase inhibitor to become available, and thus offered new options for patients with multiple resistance. The strategic use of raltegravir in this setting is examined in this study. METHODS In order to examine the efficacy of raltegravir in second and later lines of antiretroviral combinations, data for 740 patients from three clinical cohorts were analysed with a focus on the combinations that were used. These were stratified into the combination of two nonnucleoside reverse transcriptase inhibitors and raltegravir (2NRTIs + RAL), the combination of a boosted protease inhibitor and raltegravir (bPI + RAL), and other raltegravir-containing combinations. RESULTS The overall rate of virological suppression to < 50 HIV-1 RNA copies/mL was 69.5%. Although the baseline rate of virological suppression was higher for 2NRTIs + RAL than for the other strata, the outcomes were similar for all three groups at weeks 24, 48, 72 and 96. CONCLUSIONS These data indicate that, in a real-life setting, raltegravir can be used with a high virological success rate in treatment-experienced patients, and that the different combinations analysed (2NRTIs + RAL, bPI + RAL and others) show comparable rates of virological suppression.
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Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors.
Famiglini, V, Silvestri, R
Antiviral chemistry & chemotherapy. 2018;:2040206617753443
Abstract
Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5'-dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length. IAS derivatives look like promising drug candidates for the treatment of AIDS and related infections in combination with other antiretroviral agents.
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Ledipasvir-Sofosbuvir for 8 Weeks in Non-Cirrhotic Patients with Previously Untreated Genotype 1 HCV Infection ± HIV-1 Co-Infection.
Isakov, V, Gankina, N, Morozov, V, Kersey, K, Lu, S, Osinusi, A, Svarovskaia, E, Brainard, DM, Salupere, R, Orlova-Morozova, E, et al
Clinical drug investigation. 2018;(3):239-247
Abstract
UNLABELLED BACKGROUND AND OBJECTIVES The efficacy of < 12 weeks of hepatitis C virus (HCV) treatment in patients co-infected with HCV and human immunodeficiency virus type 1 (HIV-1) has not been established. We assessed the efficacy and safety of ledipasvir-sofosbuvir for 8 weeks in HCV mono-infected and HCV/HIV-1 co-infected patients. METHODS We enrolled patients mono-infected with genotype 1 HCV or co-infected with HCV and HIV-1 who were HCV treatment-naive and did not have cirrhosis. HCV/HIV-1 co-infected patients were either not receiving antiretroviral treatment and had a CD4 T-cell count > 500 cells/mm3 or were receiving a protocol-approved antiretroviral regimen for ≥ 8 weeks (or ≥ 6 months for abacavir-containing regimens) and had HIV-1 RNA < 50 copies/mL and a CD4 T-cell count > 200 cells/mm3. Patients received ledipasvir-sofosbuvir (90/400 mg) once daily for 8 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment discontinuation (SVR12). RESULTS The SVR12 rate was 100% (67/67) for HCV mono-infected patients and 97% (57/59) for HCV/HIV-1 co-infected patients. Two patients relapsed by the week 4 post-treatment visit. Overall, the most common adverse events were headache (52%) and upper abdominal pain (26%). There were no serious adverse events or treatment discontinuations due to adverse events. No HCV/HIV-1 co-infected patients receiving antiretroviral treatment experienced HIV virologic rebound, and no clinically meaningful changes in CD4 T-cell counts were observed in any co-infected patient. CONCLUSIONS Non-cirrhotic, treatment-naive patients with genotype 1 HCV mono-infection and HCV/HIV-1 co-infection achieved high rates of SVR12 with 8 weeks of treatment with ledipasvir/sofosbuvir. ClinicalTrials.gov identifier: NCT02472886.
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Modelling interaction between HIV-1 Nef and calnexin.
Adzhubei, AA, Anashkina, AA, Tkachev, YV, Kravatsky, YV, Pushkarsky, T, Kulkarni, A, Makarov, AA, Bukrinsky, MI
AIDS (London, England). 2018;(15):2103-2111
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Abstract
BACKGROUND HIV-associated atherosclerosis is a major comorbidity due, in part, to systemic effects of the virus on cholesterol metabolism. HIV protein Nef plays an important role in this pathology by impairing maturation of the main cellular cholesterol transporter ATP-Binding Cassette (ABCA) 1. ABCA1 maturation critically depends on calnexin, an integral endoplasmic reticulum membrane chaperone, and Nef binds to the cytoplasmic domain of calnexin and impairs interaction of calnexin with ABCA1. Overarching goal of the present study was to model Nef-calnexin interaction interface, and identify small molecule compounds potentially inhibiting this interaction. METHODS Molecular dynamics was utilized to build structure model of calnexin cytoplasmic domain, followed by global docking combined with application of QASDOM software developed by us for efficient analysis of receptor-ligand complexes. Structure-based virtual screening was performed for all sites identified by docking. A soluble analogue of a compound from the screening results list was tested for ability to down-regulate ABCA1. RESULTS We identified major interaction sites in calnexin and reciprocal sites in Nef. Virtual screening yielded a number of small-molecule compounds potentially blocking a calnexin site. Interestingly, one of the compounds, NSC13987, was previously identified by us as an inhibitor targeting a Nef site. An analogue of NSC13987, AMS-55, potently reversed the negative effect of Nef on ABCA1 abundance. CONCLUSIONS We have modelled Nef-calnexin interaction, predicted small molecule compounds that can potentially inhibit this interaction, and experimentally tested one of these compounds, confirming its effectiveness. These findings provide a platform for searching for new therapeutic agents to treat HIV-associated comorbidities.
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Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects.
Capetti, AF, De Socio, GV, Cossu, MV, Sterrantino, G, Cenderello, G, Cattelan, A, Baldin, GM, Soria, A, Riccardi, N, Niero, FP, et al
HIV clinical trials. 2018;(6):242-248
Abstract
BACKGROUND Dolutegravir (DTG) plus boosted darunavir (bDRV) is a compact, adherence-friendly salvage regimen with the highest genetic barrier to HIV-1 resistance. OBJECTIVE Aim of the present study is to assess the long term (96-week) safety and efficacy of DTG + bDRV in a of multidrug-experienced HIV-1 infected patients, simplifying or building rescue regimens. METHODS All HIV-1-infected subjects from eleven Italian centers switched to DTG + bDRV between March 2014 and September 2015 were included and followed for minimum 96 weeks. RESULTS The cohort comprises 130 subjects, switched from 42 different, complex or at least twice-daily regimens, mainly for simplification (44.6%), viral failure (30.0%) or toxicity (16.6%). At baseline 118 had documented resistance to 1-5 antiretroviral classes and 12 lacked genotypic results either for historical reasons or for problems with primer annealing; 52 (40%) had uncontrolled viral replication, three above 500.000 copies/mL. At week 96 two showed ≥50 HIV-1 RNA copies/mL, 23 had 1-49 copies/mL and 101 had no virus detected. The proportion of subjects presenting abnormal values at baseline significantly decreased for serum glucose, creatinine, AST, total cholesterol and triglycerides. CONCLUSIONS These long-term data confirm the reliability of the two-drug regimen consisting of bDRV plus DTG in salvage settings in HIV-1 infection.
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Exposure of the HIV-1 broadly neutralizing antibody 10E8 MPER epitope on the membrane surface by gp41 transmembrane domain scaffolds.
Oakes, V, Torralba, J, Rujas, E, Nieva, JL, Domene, C, Apellaniz, B
Biochimica et biophysica acta. Biomembranes. 2018;(6):1259-1271
Abstract
The 10E8 antibody achieves near-pan neutralization of HIV-1 by targeting the remarkably conserved gp41 membrane-proximal external region (MPER) and the connected transmembrane domain (TMD) of the HIV-1 envelope glycoprotein (Env). Thus, recreating the structure that generates 10E8-like antibodies is a major goal of the rational design of anti-HIV vaccines. Unfortunately, high-resolution information of this segment in the native Env is lacking, limiting our understanding of the behavior of the crucial 10E8 epitope residues. In this report, two sequences, namely, MPER-TMD1 (gp41 residues 671-700) and MPER-TMD2 (gp41 residues 671-709) were compared both experimentally and computationally, to assess the TMD as a potential membrane integral scaffold for the 10E8 epitope. These sequences were selected to represent a minimal (MPER-TMD1) or full-length (MPER-TMD2) TMD membrane anchor according to mutagenesis results reported by Yue et al. (2009) J. Virol. 83, 11,588. Immunochemical assays revealed that MPER-TMD1, but not MPER-TMD2, effectively exposed the MPER C-terminal stretch, harboring the 10E8 epitope on the surface of phospholipid bilayers containing a cholesterol concentration equivalent to that of the viral envelope. Molecular dynamics simulations, using the recently resolved TMD trimer structure combined with the MPER in a cholesterol-enriched model membrane confirmed these results and provided an atomistic mechanism of epitope exposure which revealed that TMD truncation at position A700 combined with N-terminal addition of lysine residues positively impacts epitope exposure. Overall, these results provide crucial insights into the design of effective MPER-TMD derived immunogens.
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Intestinal Integrity Biomarkers in Early Antiretroviral-Treated Perinatally HIV-1-Infected Infants.
Koay, WLA, Lindsey, JC, Uprety, P, Bwakura-Dangarembizi, M, Weinberg, A, Levin, MJ, Persaud, D
The Journal of infectious diseases. 2018;(7):1085-1089
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Abstract
Intestinal fatty acid binding protein (iFABP) levels did not differ between human immunodeficiency virus type 1 (HIV-1)- infected infants and uninfected infants exposed to HIV-1, but those who breastfed had substantially lower levels. Zonulin levels increased from 3 to 5.3 months of age with perinatal acquisition of HIV-1 despite early antiretroviral treatment. Biomarkers of intestinal integrity (ie, iFABP and zonulin) were compared in 56 HIV-1-positive African infants who received early antiretroviral treatment and 53 HIV-1-exposed but uninfected (HEU) controls. Despite heightened inflammation and immune activation in HIV-positive infants, iFABP and zonulin levels at 3 months of age were not different from those in HEU infants and largely were not correlated with inflammatory and immune activation biomarkers. However, zonulin levels increased and became significantly higher in HIV-positive infants as compared to HEU infants by 5 months of age, despite viral suppression due to antiretroviral treatment. These findings have implications for intestinal integrity biomarker profiling in perinatal HIV-1 infection.
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Genetic divergence of HIV-1 B subtype in Italy over the years 2003-2016 and impact on CTL escape prevalence.
Alteri, C, Fabeni, L, Scutari, R, Berno, G, Di Carlo, D, Gori, C, Bertoli, A, Vergori, A, Mastrorosa, I, Bellagamba, R, et al
Scientific reports. 2018;(1):15739
Abstract
HIV-1 is characterized by high genetic variability, with implications for spread, and immune-escape selection. Here, the genetic modification of HIV-1 B subtype over time was evaluated on 3,328 pol and 1,152 V3 sequences belonging to B subtype and collected from individuals diagnosed in Italy between 2003 and 2016. Sequences were analyzed for genetic-distance from consensus-B (Tajima-Nei), non-synonymous and synonymous rates (dN and dS), CTL escapes, and intra-host evolution over four time-spans (2003-2006, 2007-2009, 2010-2012, 2013-2016). Genetic-distance increased over time for both pol and V3 sequences (P < 0.0001 and 0.0003). Similar results were obtained for dN and dS. Entropy-value significantly increased at 16 pol and two V3 amino acid positions. Seven of them were CTL escape positions (protease: 71; reverse-transcriptase: 35, 162, 177, 202, 207, 211). Sequences with ≥3 CTL escapes increased from 36.1% in 2003-2006 to 54.0% in 2013-2016 (P < 0.0001), and showed better intra-host adaptation than those containing ≤2 CTL escapes (intra-host evolution: 3.0 × 10-3 [2.9 × 10-3-3.1 × 10-3] vs. 4.3 × 10-3 [4.0 × 10-3-5.0 × 10-3], P[LRT] < 0.0001[21.09]). These data provide evidence of still ongoing modifications, involving CTL escape mutations, in circulating HIV-1 B subtype in Italy. These modifications might affect the process of HIV-1 adaptation to the host, as suggested by the slow intra-host evolution characterizing viruses with a high number of CTL escapes.
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Inclusion body myositis and human immunodeficiency virus type 1: A new case report and literature review.
Couture, P, Malfatti, E, Morau, G, Mathian, A, Cohen-Aubart, F, Nielly, H, Amoura, Z, Cherin, P
Neuromuscular disorders : NMD. 2018;(4):334-338
Abstract
Prevalence of muscle disease in human immunodeficiency virus (HIV) infection is less than 1% of patients with acquired immune deficiency syndrome. Sporadic inclusion body myositis (IBM) is observed in a few cases of patients infected by retroviruses such as HIV-1. A Caucasian man was diagnosed with HIV when he was 30 years old. The viral load was undetectable and CD4 cell count was 600/mm3 when the diagnosis of inclusion body myositis was confirmed. Histological findings were typical of IBM. The treatment consisted of immunoglobulin therapy for three years without effect. Twenty-two patients were found in the English and French literature. They are younger than those who suffer from IBM without HIV (median age = 47, range: 30 to 59), and they are mostly men with considerable serum creatine kinase (CK) elevation (median CK level = 1322 IU/L, range: 465 to 10270), most of them were treated with Zidovudine.