Relative replication capacity of phenotypic SIV variants during primary infections differs with route of inoculation

BACKGROUND: Previous studies of human and simian immunodeficiency virus (HIV and SIV) have demonstrated that adaptive mutations selected during the course of infection alter viral replicative fitness, persistence, and pathogenicity. What is unclear from those studies is the impact of transmission on the replication and pathogenicity of the founding virus population. Using the SIV-macaque model, we examined whether the route of infection would affect the establishment and replication of two SIVmne variants of distinct in vitro and in vivo biological characteristics. For these studies, we performed dual-virus inoculations of pig-tailed macaques via intrarectal or intravenous routes with SIVmneCl8, a miminally pathogenic virus, and SIVmne027, a highly pathogenic variant that replicates more robustly in CD4(+ )T cells. RESULTS: The data demonstrate that SIVmne027 is the dominant virus regardless of the route of infection, indicating that the capacity to replicate efficiently in CD4(+ )T cells is important for fitness. Interestingly, in comparison to intravenous co-infection, intrarectal inoculation enabled greater relative replication of the less pathogenic virus, SIVmneCl8. Moreover, a higher level of SIVmneCl8 replication during primary infection of the intrarectally inoculated macaques was associated with lower overall plasma viral load and slower decline in CD4(+ )T cells, even though SIVmne027 eventually became the dominant virus. CONCLUSIONS: These results suggest that the capacity to replicate in CD4(+ )T cells is a significant determinant of SIV fitness and pathogenicity. Furthermore, the data also suggest that mucosal transmission may support early replication of phenotypically diverse variants, while slowing the rate of CD4(+ )T cell decline during the initial stages of infection

The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling

The cell cycle is coordinated with differentiation during animal development. Here we report a cell-cycle-independent developmental role for a master cell-cycle regulator, the anaphase-promoting complex or cyclosome (APC/C), in the regulation of cell fate through modulation of Wingless (Wg) signaling. The APC/C controls both cell-cycle progression and postmitotic processes through ubiquitin-dependent proteolysis. Through an RNAi screen in the developing $\textit{Drosophila}$eye, we found that partial APC/C inactivation severely inhibits retinal differentiation independently of cell-cycle defects. The differentiation inhibition coincides with hyperactivation of Wg signaling caused by the accumulation of a Wg modulator, $\textit{Drosophila}$ Nek2 (dNek2). The APC/C degrades dNek2 upon synchronous G1 arrest prior to differentiation, which allows retinal differentiation through local suppression of Wg signaling. We also provide evidence that decapentaplegic signaling may posttranslationally regulate this APC/C function. Thus, the APC/C coordinates cell-fate determination with the cell cycle through the modulation of developmental signaling pathways.T.M. and F.M. were partly supported by a CRUK Fellowship to Y.K. T.M. thanks the European Commission for a Marie Curie fellowship

GPI-anchored single chain Fv - an effective way to capture transiently-exposed neutralization epitopes on HIV-1 envelope spike

<p>Abstract</p> <p>Background</p> <p>Identification of broad neutralization epitopes in HIV-1 envelope spikes is paramount for HIV-1 vaccine development. A few broad neutralization epitopes identified so far are present on the surface of native HIV-1 envelope spikes whose recognition by antibodies does not depend on conformational changes of the envelope spikes. However, HIV-1 envelope spikes also contain transiently-exposed neutralization epitopes, which are more difficult to identify.</p> <p>Results</p> <p>In this study, we constructed single chain Fvs (scFvs) derived from seven human monoclonal antibodies and genetically linked them with or without a glycosyl-phosphatidylinositol (GPI) attachment signal. We show that with a GPI attachment signal the scFvs are targeted to lipid rafts of plasma membranes. In addition, we demonstrate that four of the GPI-anchored scFvs, but not their secreted counterparts, neutralize HIV-1 with various degrees of breadth and potency. Among them, GPI-anchored scFv (X5) exhibits extremely potent and broad neutralization activity against multiple clades of HIV-1 strains tested. Moreover, we show that GPI-anchored scFv (4E10) also exhibited more potent neutralization activity than its secretory counterpart. Finally, we demonstrate that expression of GPI-anchored scFv (X5) in the lipid raft of plasma membrane of human CD4⁺T cells confers long-term resistance to HIV-1 infection, HIV-1 envelope-mediated cell-cell fusion, and the infection of HIV-1 captured and transferred by human DCs.</p> <p>Conclusions</p> <p>Thus GPI-anchored scFv could be used as a general and effective way to identify antibodies that react with transiently-exposed neutralization epitopes in envelope proteins of HIV-1 and other enveloped viruses. The GPI-anchored scFv (X5), because of its breadth and potency, should have a great potential to be developed into anti-viral agent for HIV-1 prevention and therapy.</p

Detection of the interfacial exchange field at a ferromagnetic insulator-nonmagnetic metal interface with pure spin currents

At the interface between a nonmagnetic metal (NM) and a ferromagnetic insulator (FI) spin current can interact with the magnetization, leading to a modulation of the spin current. The interfacial exchange field at these FI-NM interfaces can be probed by placing the interface in contact with the spin transport channel of a lateral spin valve (LSV) device and observing additional spin relaxation processes. We study interfacial exchange field in lateral spin valve devices where Cu spin transport channel is in proximity with ferromagnetic insulator EuS (EuS-LSV) and yttrium iron garnet Y$_3$Fe$_5$O$_{12}$ (YIG-LSV). The spin signals were compared with reference lateral spin valve devices fabricated on nonmagnetic Si/SiO$_2$ substrate with MgO or AlO$_x$ capping. The nonlocal spin valve signal is about 4 and 6 times lower in the EuS-LSV and YIG-LSV, respectively. The suppression in the spin signal has been attributed to enhanced surface spin-flip probability at the Cu-EuS (or Cu-YIG) interface due to interfacial spin-orbit field. Besides spin signal suppression we also found widely observed low temperature peak in the spin signal at $T \sim$30 K is shifted to higher temperature in the case of devices in contact with EuS or YIG. Temperature dependence of spin signal for different injector-detector distances reveal fluctuating exchange field at these interfaces cause additional spin decoherence which limit spin relaxation time in addition to conventional sources of spin relaxation. Our results show that temperature dependent measurement with pure spin current can be used to probe interfacial exchange field at the ferromagnetic insulator-nonmagnetic metal interface.Comment: 10 pages, 3 figures, accepted in Physical Review

High-Pressure Electrical Resistivity Measurements of EuFe2As2 Single Crystals

High-pressure electrical resistivity measurements up to 3.0GPa have been performed on EuFe2As2 single crystals with residual resistivity ratios RRR=7 and 15. At ambient pressure, a magnetic / structural transition related to FeAs-layers is observed at T0 =190K and 194K for samples with RRR=7 and 15, respectively. Application of hydrostatic pressure suppresses T0, and then induces similar superconducting behavior in the samples with different RRR values. However, the critical pressure 2.7GPa, where T0=0, for the samples with RRR=15 is slightly but distinctly larger than 2.5GPa for the samples with RRR=7.Comment: To be published in J. Phys.: Conf. Se

Quasi-Two-Dimensional Fermi Surfaces and Coherent Interlayer Transport in KFe2_2As2_2

We report the results of the angular-dependent magnetoresistance oscillations (AMROs), which can determine the shape of bulk Fermi surfaces in quasi-two-dimensional (Q2D) systems, in a highly hole-doped Fe-based superconductor KFe$_2$As$_2$ with $T_c \approx$ 3.7 K. From the AMROs, we determined the two Q2D FSs with rounded-square cross sections, corresponding to 12% and 17% of the first Brillouin zone. The rounded-squared shape of the FS cross section is also confirmed by the analyses of the interlayer transport under in-plane fields. From the obtained FS shape, we infer the character of the 3d orbitals that contribute to the FSs.Comment: 4 pages, 4 figures, accepted in Phys. Rev. Let

Heavily glycosylated, highly fit SIVMne variants continue to diversify and undergo selection after transmission to a new host and they elicit early antibody dependent cellular responses but delayed neutralizing antibody responses

<p>Abstract</p> <p>Background</p> <p>Lentiviruses such as human and simian immunodeficiency viruses (HIV and SIV) undergo continual evolution in the host. Previous studies showed that the late-stage variants of SIV that evolve in one host replicate to significantly higher levels when transmitted to a new host. However, it is unknown whether HIVs or SIVs that have higher replication fitness are more genetically stable upon transmission to a new host. To begin to address this, we analyzed the <it>envelope </it>sequence variation of viruses that evolved in animals infected with variants of SIVMne that had been cloned from an index animal at different stages of infection.</p> <p>Results</p> <p>We found that there was more evolution of <it>envelope </it>sequences from animals infected with the late-stage, highly replicating variants than in animals infected with the early-stage, lower replicating variant, despite the fact that the late virus had already diversified considerably from the early virus in the first host, prior to transmission. Many of the changes led to the addition or shift in potential-glycosylation sites-, and surprisingly, these changes emerged in some cases prior to the detection of neutralizing antibody responses, suggesting that other selection mechanisms may be important in driving virus evolution. Interestingly, these changes occurred after the development of antibody whose anti-viral function is dependent on Fc-Fcγ receptor interactions.</p> <p>Conclusion</p> <p>SIV variants that had achieved high replication fitness and escape from neutralizing antibodies in one host continued to evolve upon transmission to a new host. Selection for viral variants with glycosylation and other envelope changes may have been driven by both neutralizing and Fcγ receptor-mediated antibody activities.</p