Investigating the role of Gag in protease inhibitor susceptibility amongst West African HIV-1 subtypes

HIV-1 Gag contributes to susceptibility of protease inhibitors (PIs) in the absence of known resistance mutations in the protease gene. For the majority of HIV-infected patients worldwide, PIs are the second, and last-line of therapy. Clinically, only around 20% of individuals who fail PI regimen develop major resistance mutations in protease. We previously showed that full-length Gagprotease-derived phenotypic susceptibility to PIs differed between HIV-1 CRF02_AG and subtype G-infected patients who went on to successfully suppress viral replication versus those who experienced virological failure of boosted lopinavir monotherapy as first-line treatment in a clinical trial. We hypothesised therefore that baseline PI susceptibility by Gag-protease phenotyping could be used to predict treatment outcomes for patients on second line, boosted-PI treatment in the real-world clinical setting in Nigeria, where subtypes CRF02_AG/G dominate the epidemic. We used clinical and demographic data; HIV-1subtype, sex, age, viral load, duration of treatment and baseline CD4 count to match individuals who experienced second-line failure with ritonavir-boosted PI-based ART (‘baseline failures’) to those who achieved virological response (‘baseline successes’) with virological failure defined by viral load <400 copies of HIV-1 RNA/mL by week 48. Using a single replication-cycle assay, we carried out in vitro phenotypic susceptibility testing of patient-derived viruses from these two groups. We found no impact of baseline HIV-1 Gagprotease-derived phenotypic susceptibility on outcomes of PI-based second-line ART, treatment outcome could not be predicted using baseline susceptibility alone. Secondly, we sought to explore the role of mutation in Gag-protease genotypic and phenotypic changes within patients who failed PI-based regimens without known drug resistance-associated protease mutations in order to identify novel determinants of PI resistance. We used longitudinal samples collected at baseline, and at virological failure to explore the role of Gag mutations. Using target enrichment and next-generation sequencing (NGS), followed by haplotype reconstruction and phenotypic drug assays and phylogenetic analysis, we reported for the first time a four-amino acid mutation signature in HIV-1, CRF02_AG matrix (S126del, H127del, T122A and G123E) which confer reduced susceptibility to the PI, lopinavir and atazanavir. Our multi-pronged genotypic and phenotypic approach to document emergence and temporal dynamics of a novel protease inhibitor resistance signature in HIV- 1 matrix domain reveals the interplay between Gag associated resistance and fitness

OTMM based Proposal Classification and Clustering

In the current environment, important task in any agencies (government, private) are to be selection proper search proposal. The proposal groups into the respective discipline when the large number of proposals are received .There is need to classify research proposals into proper categories automatically this will speed up the research proposal classification work. The technique used for proposals classification is OTTM Based on this respective discipline proposal assign to their expert for verification and review purpose

Transgenic Approaches for Nutritional Enhancement of Potato

Potatoes provide an excellent source of carbohydrates, minerals, vitamins, carotenoids, anthocyanins, and several other metabolites which play an important role in human nutrition. These bioactive compounds are effective in preventing diseases like cancer, diabetes, and heart-related issues. In addition to their industrial uses, potatoes are a major focus of genetic engineering programs for the modification of nutritional properties. Several important candidate genes operating in phenylpropanoid mechanism, ascorbic acid biosynthesis pathway, carbohydrate metabolism, steroidal glycoalkaloid biosynthesis pathway, and other-related metabolic steps have been cloned and characterized at the biochemical and molecular levels. Overexpression and down regulation of genes operating in these pathways has revealed important insights into improved nutritional quality. Expression of a transgene has successfully resulted in increasing carotenoids, anthocyanins, and vitamin content in transgenic tubers. Reduction in glycoalkaloid content, enzymatic browning, flesh color, and chipping quality has been achieved via modification of the genes involved in the respective biochemical pathway in potatoes. Transgenic approaches not only resulted in improved quality but also helped in understanding the biochemical and molecular mechanisms associated with the regulation of genes in these pathways. Although the commercialization of transgenic potatoes is still hindered by consumers approval and ethical restrictions, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system holds promise as a non-transgenic alternative for developing nutritionally enhanced potatoes

A Review on Topical Gels as Drug Delivery System

The clinical evidence indicates that topical gel is a safe and most effective treatment option for use in the management of skin related disease and used for local action to reduce the side effects associated with other conventional dosage form. Topical drug delivery systems include a large variety of pharmaceutical dosage form like semisolids, liquid preparation, sprays and solid powders. Most widely used semisolid preparation for topical drug delivery includes gels, creams and ointments. A gel is a cross-linked polymer network swollen in a liquid medium. Its properties depend strongly on the interaction between solid state polymer and the liquid component. Gels exhibit no steady-state flow. The interaction between polymer and the liquid dispersion medium form an interlacing three dimensional network of particles of dispersed phase. The increased viscosity caused by interlacing and consequential internal friction is responsible for the semisolid state. Topical gel formulation provides a suitable delivery system for drugs because they are less greasy and can be easily removed from the skin. Gel formulation provides better application property and stability in comparison to cream and ointments. Keywords: Topical, drug delivery, gels, review, skin. Percutaneous penetration, drug delivery, organogels, Hydrogel

HIV-1 viral load is elevated in individuals with reverse transcriptase mutation M184V/I during virological failure of first line antiretroviral therapy and is associated with compensatory mutation L74I

Background: M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance, and increased tenofovir (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against HIV-1 with these mutations possibly as a result of reduced replication capacity. Here we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside RT inhibitor (NNRTI)-containing regimen. Methods: We compared VL in absence and presence M184V/I across studies using random effects meta-analysis. The effect of mutations on virus RT activity and infectiousness was analysed in vitro. Results: M184I/V was present in 817 (56.5%) of 1445 individuals with VF. VL was similar in individuals with or without M184I/V (difference in log10VL 0.18, 95% CI 0.05-0.31). CD4 count was lower both at initiation of ART and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (p<0.0001). In vitro, L74I compensated for defective replication of M184V mutated virus. Conclusion: Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. We therefore do not find evidence for a benefit of XTC in the context of first line failure on this combination

Floating type drug delivery system: a review

Floating Type drug delivery system retains the dosage form for a long span. They provide local delivery to specific region like stomach and proximal small intestine and shows better bioavailability and improve therapeutic activity and substantial benefit to patients. FDDS is one of the novel drug delivery system to prolong gastric retention time. Various forms of gastro retentive drug delivery system, such as floating and non- floating. Keywords: Floating Drug Delivery System, Classification effervescent, non-effervescent, and Factors affecting FDDS

HIV-1 viral load is elevated in individuals with reverse transcriptase mutation M184V/I during virological failure of first line antiretroviral therapy and is associated with compensatory mutation L74I

Background: M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance, and increased tenofovir (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against HIV-1 with these mutations possibly as a result of reduced replication capacity. Here we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside RT inhibitor (NNRTI)-containing regimen. / Methods: We compared VL in absence and presence M184V/I across studies using random effects meta-analysis. The effect of mutations on virus RT activity and infectiousness was analysed in vitro. / Results: M184I/V was present in 817 (56.5%) of 1445 individuals with VF. VL was similar in individuals with or without M184I/V (difference in log10VL 0.18, 95% CI 0.05-0.31). CD4 count was lower both at initiation of ART and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (p<0.0001). In vitro, L74I compensated for defective replication of M184V mutated virus. / Conclusion: Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. We therefore do not find evidence for a benefit of XTC in the context of first line failure on this combination

Baseline PI susceptibility by HIV-1 Gag-protease phenotyping and subsequent virological suppression with PI-based second-line ART in Nigeria

Objectives: Previous work showed that gag-protease-derived phenotypic susceptibility to PIs differed between HIV-1 subtype CRF02_AG/subtype G-infected patients who went on to successfully suppress viral replication versus those who experienced virological failure of lopinavir/ritonavir monotherapy as first-line treatment in a clinical trial. We analysed the relationship between PI susceptibility and outcome of second-line ART in Nigeria, where subtypes CRF02_AG/G dominate the epidemic. Methods: Individuals who experienced second-line failure with ritonavir-boosted PI-based ART were matched (by subtype, sex, age, viral load, duration of treatment and baseline CD4 count) to those who achieved virological response (‘successes’). Successes were defined by viral load <400 copies of HIV-1 RNA/mL by week 48. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with PI susceptibility expressed as IC50 fold change (FC) relative to a subtype B reference strain. Results: The median (IQR) lopinavir IC50 FC was 4.04 (2.49–7.89) for virological failures and 4.13 (3.14–8.17) for virological successes (P = 0.94). One patient had an FC >10 for lopinavir at baseline and experienced subsequent virological failure with ritonavir-boosted lopinavir as the PI. There was no statistically significant difference in single-round replication efficiency between the two groups (P = 0.93). There was a moderate correlation between single-round replication efficiency and FC for lopinavir (correlation coefficient 0.32). Conclusions: We found no impact of baseline HIV-1 Gag-protease-derived phenotypic susceptibility on outcomes of PI-based second-line ART in Nigeria

Enhancing Privacy Preservation of Web Service through Negotiation Mechanism

ABSTRACT: Web service composition is a web technology which is use for combining the information from multiple sources into single application. With the help of this web service we can collected the large amount of data. Web Service is a technique provides a special type of composition application that aims at integrating data from multiple data provider depending on user request. DaaS depend on the specified useful data can be supplied according to the user demand. The main use of DaaS is eliminating redundancy and reduces associated expenditures. It modifies the data via single update point for multiple users. This paper proposes a formal privacy model in order to extend DaaS description with privacy capabilities. DaaS composition approach allowing verifying the compatibilities between privacy requirements and policies in DaaS composition