Low Resistance Barrier Research Articles

Anti-Monkeypox Infection Approaches: From Prevention to Therapeutic Lines.

Anti-Monkeypox Infection Approaches: From Prevention to Therapeutic Lines.

Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC50s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.

Rilpivirine: The Key for Long-term Success

During the past 30 years of antiretroviral therapy, continuous improvements in drug discovery have provided increasingly potent and safer antivirals that have transformed HIV infection in a chronic illness, rarely fatal. Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are frequently used as part of any antiretroviral combination therapy. Side effects and low resistance barrier of fi rst-generation NNRTIs (e.g., nevirapine and efavirenz) have been overcome with rilpivirine (RPV), and the last NNRTI approved for the treatment of HIV infection. The good efficacy, safety profi le, and convenient dosing of RPV account for the unique durability of RPV-based regimens. The advent of new oral fi xed-dose coformulations of RPV (e.g., along with dolutegravir or with tenofovir alafenamide [TAF]/emtricitabine [FTC]) as well as the development of long-acting injectable RPV nanoformulations will further expand its therapeutic landscape, including RPV use in dual maintenance therapy in HIV-infected patients or as pre-exposure prophylaxis in high-risk uninfected individuals.

Current progress in host innate and adaptive immunity against hepatitis C virus infection.

Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans.

The Decline in HIV-1 Drug Resistance in Heavily Antiretroviral-Experienced Patients Is Associated with Optimized Prescriptions in a Treatment Roll-Out Program in Mexico.

A decrease in the rate of acquired antiretroviral (ARV) drug resistance (ADR) over time has been documented in high-income settings, but data on the determinants of this phenomenon are lacking. We tested the hypothesis that in heavily ARV-experienced patients in the Mexican ARV therapy (ART) roll-out program, the drop in ADR would be associated with changes in ARV drug usage. Genotypic resistance tests obtained from 974 HIV-infected patients with virological failure and at least 2 previously failed ARV regimens from throughout the country were analyzed for the presence of nucleos(t)ide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitor (PI) resistance-associated mutations (RAMs). Patients were divided into two groups according to their first ART start date: 488 patients initiated ART before mid-2003 (group 1) and 486 after mid-2003 (group 2). The rate of RAMs, median resistance score of several sentinel ARVs, and composition of ART drugs in patient's entire treatment history were compared between both groups. Patients in group 2 were less likely to have >3 thymidine analogue-associated mutations (TAMs) and >3 PI-mRAMs [adjusted odds ratio (aOR) = 0.37; 95% confidence interval (95% CI) = 0.25-0.54; p < .001 and aOR = 0.53; 95% CI = 0.36-0.77; p = .001, respectively] and had a significantly lower resistance score for zidovudine, tenofovir, ritonavir-boosted (r)-lopinavir, r-atazanavir, and r-darunavir than group 1 patients. A significantly lower proportion of patients in group 2 used monotherapy, bitherapy, thymidine analogue-containing regimens, nonboosted PI-containing regimens, and low resistance barrier PI-containing regimens. In Mexican ARV-experienced patients, the occurrence of TAM and PI-mRAM has significantly declined over time. This can be explained by treatment optimization in the national ART roll-out program in recent years.

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure, an expert review

ABSTRACTHepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct – acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA – Dasabuvir, a non – nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven – Johnson syndrome) and strong inducers of CYP3A and CYP2CB.

Strategic use of lamivudine in the management of chronic hepatitis B

Lamivudine is no longer recommended as first-line therapy for chronic hepatitis B. The same advice has been made for adefovir and telbivudine, due to their relatively weak anti-viral activity and low resistance barrier, respectively. Instead, either tenofovir or entecavir is the currently preferred anti-HBV agent, given their potent anti-viral activity and high barrier to resistance. However, these drugs are expensive and their long-term use is often unaffordable for many individuals, including most patients in developing regions, where hepatitis B is generally much more prevalent. Herein, we argue that lack of universal access to the current best anti-viral drugs for hepatitis B should not imply a suboptimal management of chronic hepatitis B which denies therapy to persons who really need it. A wise and strategic use of lamivudine may provide an opportunity to bring the benefit of therapy to large HBV-infected populations, while reducing health care costs.

Controlled mechanical AFM machining of two-dimensional electron systems: fabrication of a single-electron transistor

By mechanical scratching the surface of a GaAs/AlGaAs heterostructure with an atomic force microscope an energetic barrier for the two-dimensional electron gas is formed. The barrier formation is in-situ controlled by measuring the room-temperature resistance across the barrier. Barrier heights can be tuned from some mV up to more than 100 mV as determined by measurement of the thermally activated current. Low-resistance barriers show typical tunneling behaviour at low temperatures whereas high-resistance lines show G Ω resistances in a bias range up to some 10 V allowing their use as in-plane gates. Transport measurements of a side gated single-electron transistor fabricated this way are presented.

The efficacy of filters used in respiratory function apparatus

The ability of two low resistance barrier filters (Collins DC-1 and Pall Pf 305) to remove bacteria from expired air was assessed. A specially designed coupling device was used to hold each filter or a disposable plain cardboard mouthpiece a fixed distance (4·5 cm) from a blood agar plate. Volunteers performed maximal forced vital capacity manoeuvres through the assembled apparatus and bacteria impinged on to the agar plate were enumerated. Both filters allowed the transmission of approximately one-third of expired colony forming units. The efficacy of these filters for reducing the likelihood of cross-infection during spirometry is not supported by this study.