Resistance to novel drug classes

Understanding the mechanisms that underlie resistance development to novel drugs is essential to a better clinical management of resistant viruses and to prevent further resistance development and spread. RECENT FINDINGS: Integrase inhibitors and CCR5 antagonists are the more recent antiretroviral classes developed. The HIV-1 integrase, responsible for the chromosomal integration of the newly synthesized double-stranded viral DNA into the host genomic DNA, represents a new and important target; and two integrase inhibitors (INIs), raltegravir and elvitegravir, have been shown promising results in clinical trials. Viral entry is also an attractive step for the development of new drugs against HIV variants resistant to current antiretroviral drugs, and two CCR5 antagonists have been designed to inhibit HIV-1 binding to R5 co-receptor and are under clinical investigation. SUMMARY: Drug resistance to INIs occurs through the selection of mutations within HIV integrase. The kinetic of selection seems rapid and one mutation alone is able to confer resistance to integrase inhibitor, suggesting that this class of drug has a low genetic barrier. Two ways could explain the failure of the CCR5 antagonist class: a rapid outgrowth of pre-existing archived X4 virus or the selection of a resistance to CCR5 antagonists through amino acid changes in V

GHASP: an Hα\alpha kinematic survey of spiral galaxies - X. Surface photometry, decompositions and the Tully-Fisher relation in the Rc-band

We present Rc-band surface photometry for 170 of the 203 galaxies in GHASP, Gassendi H-Alpha survey of SPirals, a sample of late-type galaxies for which high-resolution Fabry-Perot H{\alpha} maps have previously been obtained. Our data set is constructed by new Rc-band observations taken at the Observatoire de Haute-Provence (OHP), supplemented with Sloan Digital Sky Survey (SDSS) archival data, obtained with the purpose of deriving homogeneous photometric profiles and parameters. Our results include Rc-band surface brightness profiles for 170 galaxies and $ugriz$ profiles for 108 of these objects. We catalogue several parameters of general interest for further reference, such as total magnitude, effective radius and isophotal parameters -- magnitude, position angle, ellipticity and inclination. We also perform a structural decomposition of the surface brightness profiles using a multi-component method in order to separate disks from bulges and bars, and to observe the main scaling relations involving luminosities, sizes and maximum velocities. We determine the Rc-band Tully Fisher relation using maximum velocities derived solely from H$\alpha$ rotation curves for a sample of 80 galaxies, resulting in a slope of $-8.1 \pm 0.5$, zero point of $-3.0 \pm 1.0$ and an estimated intrinsic scatter of $0.28 \pm 0.07$. We note that, different from the TF-relation in the near-infrared derived for the same sample, no change in the slope of the relation is seen at the low-mass end (for galaxies with $V_{max} < 125$ km/s). We suggest that this different behaviour of the Tully Fisher relation (with the optical relation being described by a single power-law while the near-infrared by two) may be caused by differences in the stellar mass to light ratio for galaxies with $V_{max} < 125$ km/s.Comment: 17 pages, 11 figure

The multifactorial pathways towards resistance to the cytosine analogues emtricitabine and lamivudine: Evidences from literature

The article by Bulteel et al.,1 published in the September issue of the journal, has investigated the rate of M184V emergence in patients receiving HAART combinations containing efavirenz (EFV), tenofovir (TDF) and lamivudine (3 TC) or emtricitabine (FTC) within the UK Collaborative HIV Cohort. By analyzing 304 genotypic resistance tests, the authors asserted that, although patients receiving 3 TC-based regimens were more likely to develop M184V than those receiving FTC-based regimens (event rate: 0.55 [95%CI: 0.28–0.96] for 3 TC versus 0.34 [95%CI: 0.21–0.46] for FTC), this association was not statistically significant in both univariable and multivariable models. These results are different from those reported in previous studies from our and other groups2, 3 and 4 showing a significant decrease in M184V emergence in patients failing FTC + TDF-based compared to 3 TC + TDF-based HAART (Table 1). The lower prevalence of M184V in FTC-containing regimen was also supported by a recently published letter showing a strong trend (P = 0.051) towards higher rates of resistance to the 3 TC containing regimen 5.5 (1.8–12.8) per 1000 patient years when compared with the FTC containing regimens 1.7 (0.8–3.2) per 1000 patient year

Anemia in type 2 diabetic patients and correlation with kidney function in a tertiary care sub-Saharan African hospital: a cross-sectional study

BackgroundAnemia is common in diabetic patients and increases morbidity and mortality, but its burden has been less well characterized in sub-Saharan Africans. We determined the prevalence of anemia and investigated the related factors, with a particular focus on the role of declining renal function, in type 2 diabetic patients attending a tertiary health care institution in Cameroon.MethodsHemoglobin (Hb) levels were measured in a consecutive sample of patients with type 2 diabetes, who reported for annual review at the outpatient section of the Douala General Hospital in 2013. Patients were classified as anemic according to the World Health Organisation criteria (Hb < 12g/dl for females and Hb < 13g/dl for males). Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease Study Group formula. Determinants of Hb concentration and anemia were investigated using multivariable logistic regressions.ResultsA total of 636 patients were examined including 263 (prevalence rate 41.4%) who had anemia. The prevalence of anemia increased significantly with deteriorating kidney function, although up to 31.9% of patients with normal kidney function had anemia. Compared with their non-anemic counterparts, anemic diabetic patients were older, had longer duration of diabetes, lower eGFR, higher prevalence of proteinuria and diabetic retinopathy (all p < 0.05). In multivariable logistic regressions, eGFR (p = 0.001) and presence of retinopathy (p = 0.023) were the independent determinants of prevalent anemia.ConclusionsThe prevalence of anemia is high in type 2 diabetic patients attending referral institutions in Cameroon, including among those without chronic kidney disease. Routine screening for anemia in all diabetic patients may aid early identification and correction as appropriate

Comparative replication capacity of raltegravir-resistant strains and antiviral activity of the new-generation integrase inhibitor dolutegravir in human primary macrophages and lymphocytes

To evaluate the replication capacity and phenotypic susceptibility to dolutegravir and raltegravir of wild-type and raltegravir-resistant HIV-1 strains in several cellular systems

Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients

Objectives To compare the frequency of previously in vitro-selected integrase mutations (T124A, T124A/S153F, S153Y, T124A/S153Y and L101I/T124A/S153Y) conferring resistance to S/GSK1349572 between HIV-1 subtype B integrase inhibitor (INI)-naive and raltegravir-treated patients. Methods Integrase sequences from 650 INI-naive patients and 84 raltegravir-treated patients were analysed. Results The T124A mutation alone and the combination T124A/L101I were more frequent in raltegravir-failing patients than in INI-naive patients (39.3% versus 24.5%, respectively, P = 0.005 for T124A and 20.2% versus 10.0%, respectively, P = 0.008 for T124A/L101I). The S153Y/F mutations were not detected in any integrase sequence (except for S153F alone, only detected in one INI-naive patient). Conclusions T124A and T124A/L101I, more frequent in raltegravir-treated patients, could have some effect on raltegravir response and their presence could play a role in the selection of other mutations conferring S/GSK1349572 resistance. The impact of raltegravir-mediated changes such as these on the virological response to S/GSK1349572 should be studied further

Modeling the radial abundance distribution of the transition galaxy ngc 1313

NGC 1313 is the most massive disk galaxy showing a flat radial abundance distribution in its interstellar gas, a behavior generally observed in magellanic and irregular galaxies. We have attempted to reproduce this flat abundance distribution using a multiphase chemical evolution model, which has been previously used sucessfully to depict other spiral galaxies along the Hubble morphological sequence. We found that it is not possible to reproduce the flat radial abundance distribution in NGC 1313, and at the same time, be consistent with observed radial distributions of other key parameters such the surface gas density and star formation profiles. We conclude that a more complicated galactic evolution model including radial flows, and possibly mass loss due to supernova explosions and winds, is necessary to explain the apparent chemical uniformity of the disk of NGC 1313Comment: 14 paginas, 4 figures, to be published in ApJ, apri

The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation

Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway. Here, we investigated the viral DNA kinetics for mutants identified in Raltegravir-resistant patients. We found that (i) integration is impaired for Q148H when compared with the wild-type, G140S and G140S/Q148H mutants; and (ii) the N155H and G140S mutations confer lower levels of resistance than the Q148H mutation. We also characterized the corresponding recombinant INs properties. Enzymatic performances closely parallel ex vivo studies. The Q148H mutation ‘freezes’ IN into a catalytically inactive state. By contrast, the conformational transition converting the inactive form into an active form is rescued by the G140S/Q148H double mutation. In conclusion, the Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G140S/Q148H context. Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir

The Hubble Space Telescope Extragalactic Distance Scale Key Project. X. The Cepheid Distance to NGC 7331

The distance to NGC 7331 has been derived from Cepheid variables observed with HST/WFPC2, as part of the Extragalactic Distance Scale Key Project. Multi-epoch exposures in F555W (V) and F814W (I), with photometry derived independently from DoPHOT and DAOPHOT/ALLFRAME programs, were used to detect a total of 13 reliable Cepheids, with periods between 11 and 42 days. The relative distance moduli between NGC 7331 and the LMC, imply an extinction to NGC 7331 of A_V = 0.47+-0.15 mag, and an extinction-corrected distance modulus to NGC 7331 of 30.89+-0.14(random) mag, equivalent to a distance of 15.1 Mpc. There are additional systematic uncertainties in the distance modulus of +-0.12 mag due to the calibration of the Cepheid Period-Luminosity relation, and a systematic offset of +0.05+-0.04 mag if we applied the metallicity correction inferred from the M101 results of Kennicutt et al 1998.Comment: To be published in The Astrophysical Journal, 1998 July 1, v501 note: Figs 1 and 2 (JPEG files) and Fig 7 (multipage .eps file) need to be viewed/printed separatel

A Counter-rotating Bulge in the Sb Galaxy NGC 7331

We have found that the bulge of the large, nearby Sb galaxy NGC 7331 rotates retrograde to its disk. Analysis of spectra in the region of the near-IR Ca II triplet along the major axis shows that, in the radial range between 5'' and ~20'', the line of sight velocity distribution of the absorption lines has two distinct peaks, and can be decomposed into a fast-rotating component with v/sigma > 3, and a slower rotating, retrograde component with v/sigma between 1 -- 1.5. The radial surface brightness profile of the counter-rotating component follows that of the bulge, obtained from a 2-dimensional bulge-disk decomposition of a near-infrared K-band image, while the fast rotating component follows the disk. At the radius where the disk starts to dominate the isophotes change from being considerably boxy to very disky. Although a number of spiral galaxies have been found that contain cold, couter-rotating disks, this is the first galaxy known to have a boxy, probably triaxial, fairly warm, counter-rotating component, which is dominating in the central regions. If it is a bar seen end-on, this bar has to be thicker than the disk. We find that NGC 7331, even though it is a fairly early-type spiral, does not have a conventional, co-rotating bulge. The fact that the inner component is retrograde makes us believe that it was formed from infalling material, in either stellar or gaseous form (e.g. Balcells & Quinn 1990). Another possibility however is that the structure has been there since the formation of the galaxy. In this case it will be a challenge to explain the large change in orientation of the angular momentum when going outward radially.Comment: 13 pages latex, including 4 figures and 1 B/W plate. Accepted for Astrophysical Journal Letters. Revised version incorporating some small last-minute change