Similar Replicative Fitness Is Shared by the Subtype B and Unique BF Recombinant HIV-1 Isolates that Dominate the Epidemic in Argentina

The HIV-1 epidemic in South America is dominated by pure subtypes (mostly B and C) and more than 7 BF and BC recombinant forms. In Argentina, circulating recombinant forms (CRFs) comprised of subtypes B and F make up more than 50% of HIV infections. For this study, 28 HIV-1 primary isolates were obtained from patients in Buenos Aires, Argentina and initially classified into subtype B (n = 9, 32.1%), C (n = 1, 3.6%), and CRFs (n = 18, 64.3%) using partial pol and vpu-env sequences, which proved to be inconsistent and inaccurate for these phylogenetic analyses. Near full length genome sequences of these primary HIV-1 isolates revealed that nearly all intersubtype BF recombination sites were unique and countered previous “CRF” B/F classifications. The majority of these Argentinean HIV-1 isolates were CCR5-using but 4 had a dual/mixed tropism as predicted by both phenotypic and genotypic assays. Comparison of the replicative fitness of these BF primary HIV-1 isolates to circulating B, F, and C HIV-1 using pairwise competitions in peripheral blood mononuclear cells (PBMCs) indicated a similarity in fitness of these BF recombinants to subtypes B and F HIV-1 (of the same co-receptor usage) whereas subtype C HIV-1 was significantly less fit than all as previously reported. These results suggest that the multitude of BF HIV-1 strains present within the Argentinean population do not appear to have gained replicative fitness following recent B and F recombination events.     

Depletion of K-Ras promotes proteasome degradation of survivin

Mutant K-Ras and survivin both contribute to oncogenesis, but little is known about K-Ras requirement for the maintenance of the high levels of survivin in human tumors. Here we demonstrate that K-Ras depletion significantly decreases survivin levels in human cancer cells that harbor mutant but not wild type K-Ras. K-Ras depletion attenuates both basal and drug-induced survivin levels. The mechanism by which K-Ras depletion decreases survivin levels is through ubiquitination and proteasomal degradation of survivin and is independent of survivin-Thr-34 phosphorylation. Depletion of RalA and RalB, but not Raf-1, Akt1 and Akt2, decreases survivin levels, suggesting that K-Ras may regulate survivin stability through its RalGDS/Ral but not PI3K/Akt and Raf-1/Mek effector pathways. Furthermore, the ability of mutant K-Ras to induce anchorage-independent growth, invasion and survival is compromised by depletion of survivin. These studies suggest that mutant K-Ras contributes to the maintenance of the aberrantly high levels of survivin in tumors by regulating its stability, and that the ability of mutant K-Ras to induce malignant transformation is, at least in part, dependent on these high levels of survivin.     

Enzyme inhibitor modeling with TpZn complexes of functional hydroxamates and oximates

Salicylhydroxamic acid reacts with the enzyme model Tp^Ph,MeZn-OH to form the O,O-chelating hydroxamate complex 1. The hydrogen bonding capacity of zinc enzyme bound hydroxamates is reproduced by cocrystallization of two molecules if 1 with two molecules of methanol and by cocrystallization of one molecule of Tp^Ph,MeZn-acetohydroxamate with one molecule of 3-phenyl-5-methylpyrazole. The complex formed from Tp^Ph,MeZn-OH and N-tosylproline hydroxamic acid, according to its spectra, contains the hydroxamate as an N,N-chelating ligand. In contrast, the oximate derived from pyruvic aldehyde does not act as a chelating ligand, but is monodentate via the oximate oxygen.     

Effects of spatial distribution on plant associational defense against herbivory

Several studies have shown that consumption of a focal plant by herbivores depends not only on its own defense traits but also on the characteristics of the neighboring plants. A number of studies have reported on plant associational defense in relation to neighboring plant palatability but the effect of the spatial distribution of the focal plant within patches of different neighboring plants has received less attention. We conducted a manipulative experiment to determine whether and how spatial distribution of focal plants affects the associational defense between plant species. In our experimental setup sheep encountered two patches varying in spatial distribution of the focal plant within patches (dispersed or clumped) and patch quality, good patch and bad patch, where the focal plant, Lathyrus quinquenervius, was neighbored to high- (Chloris virgata) or low-palatable (Kalimeris integrifolia) species, respectively. Results showed that, when focal plants were dispersed within both patches, the risk of attack was significantly lower for focal plants in the patches with low- than high-palatable neighbors, indicating associational defense. Alternatively, when focal plants were clumped within both patches, they were consumed in bad-patch as much as in good-patch plots, which indicates the absence of associational defense. However, if the focal plants have different spatial distributions in the two patches (dispersed in good-patch and clumped in bad-patch or vice versa), sheep foraging success for focal plants was greatly reduced in dispersed spatial pattern irrespective of the palatability of neighboring plants. Therefore, we concluded that spatial distribution is as important as traits of neighboring plants in predicting vulnerability of the focal plant to grazing by generalist herbivores. The outcome of plant associational defense for different types of neighborhood strongly depends on the magnitude of herbivore foraging selectivity between and within patches, which further depended on the contrasts between plant species or between patches.     

The replicative fitness of primary human immunodeficiency virus type 1 (HIV-1) group M, HIV-1 group O, and HIV-2 isolates

The main (M) group of human immunodeficiency virus type 1 (HIV-1) is responsible for the global AIDS epidemic while HIV-1 group O (outlier) and HIV type 2 are endemic only in west and central Africa. The failure of HIV-2 and especially HIV-1 group O to spread following the initial zoonotic jumps is not well understood. This study was designed to examine the relative replicative capacities between these human lentiviruses. A pairwise competition experiment was performed with peripheral blood mononuclear cells with eight HIV-2 isolates, 6 group O viruses, and 15 group M viruses of subtype A (2 viruses), B (5 viruses), C (4 viruses), D (2 viruses) and CRF01_AE (2 viruses). HIV-1 group M isolates of any subtype were typically 100-fold-more fit than group O or HIV-2 strains when competed in peripheral blood mononuclear cells from various humans. This order in replicative fitness was also observed when virus pairs were added to human dendritic cells and then cocultured with primary, quiescent T cells, which is the model for HIV-1 transmission. These results suggest that reduced replicative and transmission fitness may be contributing to the low prevalence and limited geographical spread of HIV-2 and group O HIV-1 in the human population.