Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat

Background: The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient’s failure to respond correlated with baseline polymorphisms at SP1 residues 6-8. Results: In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance and SP1-V7M and T8Δ mutations conferred intermediate levels of BVM resistance. Conclusions: Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.Publisher PDFPeer reviewe

Dynamics of HIV-1 Assembly and Release

Assembly and release of human immunodeficiency virus (HIV) occur at the plasma membrane of infected cells and are driven by the Gag polyprotein. Previous studies analyzed viral morphogenesis using biochemical methods and static images, while dynamic and kinetic information has been lacking until very recently. Using a combination of wide-field and total internal reflection fluorescence microscopy, we have investigated the assembly and release of fluorescently labeled HIV-1 at the plasma membrane of living cells with high time resolution. Gag assembled into discrete clusters corresponding to single virions. Formation of multiple particles from the same site was rarely observed. Using a photoconvertible fluorescent protein fused to Gag, we determined that assembly was nucleated preferentially by Gag molecules that had recently attached to the plasma membrane or arrived directly from the cytosol. Both membrane-bound and cytosol derived Gag polyproteins contributed to the growing bud. After their initial appearance, assembly sites accumulated at the plasma membrane of individual cells over 1–2 hours. Assembly kinetics were rapid: the number of Gag molecules at a budding site increased, following a saturating exponential with a rate constant of ∼5×10−3 s−1, corresponding to 8–9 min for 90% completion of assembly for a single virion. Release of extracellular particles was observed at ∼1,500±700 s after the onset of assembly. The ability of the virus to recruit components of the cellular ESCRT machinery or to undergo proteolytic maturation, or the absence of Vpu did not significantly alter the assembly kinetics

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

La répartition de la population en Allemagne fédérale : concentration à l'échelle nationale et dispersion à l'échelle locale

Grossrdumige Konzentration und kleinräumige Dispersion der Bevölkerungsverteilung in der Bundesrepublik Deutschland. — In der Bundesrepublik Deutschland hait seit den frühen 60er Jahren die großräumige Konzentration der Bevolkerung in den zentralgelegenen Verdichtungsräumen und damit verbunden die Entleerung der peripheren ländlichen Räume an. Gleichzeitig sinkt die Siedlungsdichte in den großen Kernstädten der Verdichtungsräume zunehmend ab, womit eine immer weiter ausgreifende Suburbanisierung im Umland verbunden ist. Seit 1973 hat die niedrige Fruchtbarkeit verbunden mit dem Amverbestopp fur ausländische Arbeitskräfte, dazu gefûhrt, daß der Geburtenüberschuß in den ländlichen Räumen nicht mehr ausreicht, um die Abwanderungen zu egalisieren. In den groBen Verdichtungsräumen genugt die Zuwanderung aus dem Ausland und aus den ländlichen Räumen des Bundesgebietes nicht mehr, um Bevölkerungsverluste insgesamt zu vermeiden. In dieser Situation ist der Konkurrenzkampf der Regionen und der Gemeinden untereinander um Einwohner in voiler Schärfe entbrannt. Dies hat Rückwirkungen auf die Leitziele in Raumordnungspolitik und Stadtentwicklungspolitik. Die Forderung, die peripheren lândlichen Râume bewuBt leerlaufen zu lassen, gewinnt an Anhängern. Dies ist gleichwohl irrational und unrealistisch zugleich, da die Mobilisierbarkeit der dort lebenden Bewohner iiberschätzt und die damit verbundenen sozialen Konflikte bagatellisiert werden. Gleichzeitig erscheint es nicht plausibel, daß die großen Verdichtungsräume ihre Strukturprobleme mit Bevölkerungswachstum leichter bewältigen können.The distribution of the population in the German Federal Republic : concentration on the national level and dispersal on the local level. — Since the beginning of the sixties, a concentration on the national level of the population of West Germany has been going on to the advantage of great urban regions. Consequently surrounding rural areas are emptying. Simultaneously density in the large towns-centres is diminishing, in relation with a suburbanization which is encroaching ever more on the environment. Since 1973 because of the drop in the birth rate and the cessation of hiring of foreign workers, the surplus of births in rural areas no longer manages to compensate for the migration. In the large zones of urban concentration the immigration of foreigners and people from the rural areas is no longer sufficient to stave off population losses : on account of this, there has been an unleashing of competition amongst regions and towns to attract the most inhabitants; with counter-effects for the principle objectives of planning and urban development policies. The idea of freely abandonning surrounding rural areas to their fate, is gaining supporters. An attitude which is as irrational as it is unrealistic, since it overestimates the possibility of mobilizing the inhabitants of these areas and it doesn't consider seriously the social conflicts which would result. Moreover, it doesn't seem reasonable to think that large zones of urban concentration can resolve their structural problems if their population continues to grow.Une concentration à l'échelle nationale de la population se poursuit, depuis le début des années 1960, en Allemagne Fédérale, au profit des zones d'agglomération urbaine. Par voie de conséquence, les espaces ruraux périphériques se vident. Simultanément la densité dans les grandes villes-centres diminue, en rapport avec une suburbanisation qui mord toujours davantage sur l'environnement. Depuis 1973, la baisse de la fécondité et l'arrêt de l'embauche de travailleurs étrangers font que l'excédent des naissances des espaces ruraux n'arrive plus à compenser l'émigration. Dans les grandes zones de concentration urbaine l'immigration d'étrangers et de ruraux ne suffit plus à éviter des pertes de population : de là, un déchaînement de la concurrence entre régions et communes pour attirer le plus possible d'habitants, avec des effets en retour sur les objectifs principaux de la politique d'aménagement du territoire et de développement urbain. L'idée d'abandonner volontairement les espaces ruraux périphériques à leur destin gagne des partisans. Attitude aussi irrationnelle qu'irréaliste, car elle surestime la possibilité de mobiliser les habitants de ces espaces et traite à la légère les conflits sociaux qui s'ensuivraient. Par ailleurs, il ne semble pas raisonnable de penser que les grandes zones de concentration urbaine puissent résoudre leurs problèmes de structures si leur population continue de croître.Ganser Karl. La répartition de la population en Allemagne fédérale : concentration à l'échelle nationale et dispersion à l'échelle locale. In: Espace géographique, tome 7, n°3, 1978. La géographie allemande contemporaine. pp. 209-217