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Effective combination antiretroviral therapy controls HIV-1 infection but fails to eliminate latent viral reservoirs that give rise to viremia upon treatment interruption. Strategies to eradicate latently infected cells require a better understanding of their biology and distinguishing features to promote their elimination.

Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.

Significance Evidence suggests that HIV-1 disease progression is determined in the early stages of infection. Here, preinfection invariant natural killer T (iNKT) cell levels were predictive of the peak viral load during acute HIV-1 infection (AHI). Furthermore, iNKT cells were preferentially lost in AHI. This was particularly striking in the colonic mucosa, where iNKT cells were depleted more profoundly than conventional CD4+ T cells. The initiation of antiretroviral therapy during AHI-prevented iNKT cell dysregulation in peripheral blood but not in the colonic mucosa. Overall, our results support a model in which iNKT cells are early and preferential targets for HIV-1 infection during AHI., Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death–associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.

Summary Background HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection. Methods We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20–50 years, had initiated ART during acute infection (ie, Fiebig stages I–III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 106 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov , number NCT02664415 . This trial is completed. Findings Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks. Interpretation VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets. Funding US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre.

Background Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection. Methods Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I–III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls. Results In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation. Conclusions β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells., We demonstrate that memory CD4+ T cells expressing high levels of integrin β7 are enriched in total and integrated HIV-1 DNA compared to β7negative cells, and that preferential targeting of β7high cells is associated with their activation status.

This paper is devoted to increasing the accuracy of forecasting the solar power plants generation in Russia in a data-constrained environment. Within this study, an analysis of forecasting parameters influence on the solar power plants generation based on the regression analysis methods was made. The study object was a real power system, with the installed capacity of 3915 MW, 330 MW of which is the solar power plants’ share. The study also analyzed the change in the average price indice of the balancing market in Russia, depending on solar power plants presence.

To achieve higher hydrogen storage capacity than that of compressed gas vessels, new advanced materials must be developed. Among the most promising are two-dimensional layered nanomaterials, such as graphene and boron nitride, storing hydrogen via physisorption which is potentially reversible at relatively low pressures. Unlike graphene, boron nitride is a polar material that makes it potentially more attractive for hydrogen physisorption. To quickly evaluate storage capacity of novel materials an efficient theoretical tool is proposed. A customized model combining quantum simulation with thermodynamic calculation is developed and applied for pristine and oxygen-doped boron nitride materials. It is shown that pristine boron nitride has a maximum reversible hydrogen storage capacity of 1.5 wt.% under 5 MPa at room temperature. Oxygen doping increases the capacity to 1.9 wt.% under the same conditions by deepening and widening the adsorption potential. Both gravimetric and volumetric storage properties are found to be strong functions of the interlayer separation distance of the material, with an optimum distance near 7 A. The present results indicate that pristine and oxygen doped boron nitride materials have a suitable base configuration for potentially high reversible hydrogen storage.

HIV-1 Vpu decreases the exposure of epitopes within the viral envelope glycoprotein (Env) on the surface of infected cells by downregulating both BST2 and CD4. To test the hypothesis that inhibiting Vpu activity would increase the exposure of these epitopes and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC), we treated cells with the Nedd8 activation enzyme (NAE) inhibitor MLN4924, which inhibits the cullin1-based ubiquitin ligase complex coopted by Vpu to degrade cellular targets. Treatment of HeLa cells with MLN4924 or expression of a dominant negative mutant of cullin1 inhibited the Vpu-mediated downregulation of CD4 but not the downregulation of BST2. NAE inhibition also increased the surface exposure of CD4-induced epitopes within Env on HEK293 cells containing an inducible HIV genome, on infected CEM T cells, and on infected primary T cells. In contrast, the Vpu-mediated downregulation of BST2 was substantially inhibited by MLN4924 only when T cells were treated with alpha interferon (IFN-α) to induce high levels of BST2 expression. As reported previously, the absence of vpu or nef and even more so the combined absence of these two genes sensitized infected cells to ADCC. However, NAE inhibition affected ADCC minimally. Paradoxically, even in infected, IFN-treated cells in which NAE inhibition substantially rescued the surface level of BST2, the surface level of Env detected with an antibody recognizing a CD4-independent epitope (2G12) was minimally increased. Mutation of the C-terminal Vpu residue W76, which supports the ability of Vpu to stimulate virion release by displacing BST2 from assembly sites on the plasma membrane by a cullin1-independent mechanism, increased the exposure of Env detected by 2G12 on infected T cells. Thus, inhibiting the displacement function of Vpu together with its ability to degrade CD4 and BST2 may be required to sensitize infected cells to ADCC. IMPORTANCE Pathogenic viruses encode gene products that enable evasion of host immune surveillance mechanisms. One such mechanism is antibody-dependent cellular cytotoxicity (ADCC), whereby host antibodies bind envelope glycoproteins of the virus that are inserted into the cellular membrane and direct the destruction of infected cells. Targeting pharmacologically the activity of HIV-1 Vpu, which contributes to evasion of ADCC, could potentially sensitize infected cells to this immune surveillance mechanism, an outcome that would have therapeutic implications with respect to the goal of curing HIV-1 infection. The Nedd8 activation enzyme inhibitor MLN4924 blocks the activity of the host ubiquitin ligase that Vpu coopts to direct the degradation of CD4 and BST2. We observed that while MLN4924 partially reverses the activity of Vpu and could become part of a therapeutic approach by virtue of CD4-induced epitope exposure, sufficient Vpu activity as an antagonist of BST2 persists despite this drug to allow escape from ADCC.

We present a theoretical study of hydrogen adsorption on pristine graphene in the range of 0.1 to 50 MPa pressure at room temperature of 300 K by means of high accuracy molecular dynamics (MD) simulation in the LAMMPS software package1. For that we developed a novel technique of fast Force Field (FF) construction from quantum calculations. For the task, graphene-hydrogen interaction potential, constructed from quantum Density Functional Theory (DFT) calculations, was accompanied by Morse potential approximation of Silvera-Goldman potential2 for hydrogen-hydrogen interaction. We found that excessive hydrogen adsorption reaches maximum of 1.96 w.t. % at 30 MPa pressure. The isotherm of excessive hydrogen adsorption is well described by Langmuir isotherm with addition of negative linear term to account for excessive nature of adsorption. Comparison with literature data3-6 is provided. References: Plimpton, J. Comp. Phys., 117, 1 (1995). F. Silvera and V. V. Goldman, J. Chem. Phys., 69, 4209 (1978). Kowalczyk, H. Tanaka, R. Hołyst, K. Kaneko, T. Ohmori, and J. Miyamoto, J. Phys. Chem. B, 109, 17174 (2005). Patchkovskii, J. S. Tse, S. N. Yurchenko, L. Zhechkov, T. Heine, and G. Seifert, PNAS, 30, 10439 (2005). Srinivas, Y. Zhu, R. Piner, N. Skipper, M. Ellerby, and R. Ruoff, Carbon, 48, 630 (2010). C. Ruiz-García, J. Pérez-Carvajal, A. Berenguer-Murcia, M. Darder, P. Aranda, D. Cazorla-Amorós, and E. Ruiz-Hitzky, Phys. Chem. Chem. Phys., 15, 18635 (2013). Figure 1

Single-cell analysis is an important tool for dissecting heterogeneous populations of cells. The identification and isolation of rare cells can be difficult. To overcome this challenge, a methodology combining indexed flow cytometry and high-throughput multiplexed quantitative polymerase chain reaction (qPCR) was developed. The objective was to identify and characterize simian immunodeficiency virus (SIV)-infected cells present within rhesus macaques. Through quantitation of surface protein by fluorescence-activated cell sorting (FACS) and mRNA by qPCR, virus-infected cells are identified by viral gene expression, which is combined with host gene and protein measurements to create a multidimensional profile. We term the approach, targeted Single-Cell Proteo-transcriptional Evaluation, or tSCEPTRE. To perform the method, viable cells are stained with fluorescent antibodies specific for surface markers used for FACS isolation of a cell subset and/or downstream phenotypic analysis. Single cells are sorted followed by immediate lysis, multiplex reverse transcription (RT), PCR pre-amplification, and high throughput qPCR of up to 96 transcripts. FACS measurements are recorded at the time of sorting and subsequently linked to the gene expression data by well position to create a combined protein and transcriptional profile. To study SIV-infected cells directly ex vivo, cells were identified by qPCR detection of multiple viral RNA species. The combination of viral transcripts and the quantity of each provide a framework for classifying cells into distinct stages of the viral life cycle (e.g., productive versus non-productive). Moreover, tSCEPTRE of SIV+ cells were compared to uninfected cells isolated from the same specimen to assess differentially expressed host genes and proteins. The analysis revealed previously unappreciated viral RNA expression heterogeneity among infected cells as well as in vivo SIV-mediated post-transcriptional gene regulation with single-cell resolution. The tSCEPTRE method is relevant for the analysis of any cell population amenable to identification by expression of surface protein marker(s), host or pathogen gene(s), or combinations thereof.

A simple thermodynamical model taking into account non-ideality and inhomogeneity of absorbed hydrogen molecular gas has been proposed to calculate hydrogen storage capacity in carbon nanostructures as a function of temperature and pressure. The model utilizing the effective interaction potential of the hydrogen molecule with the atoms of the considered material, is based on the experimental equation of state and a local density approximation for molecular hydrogen. We have applied the model for the search of the optimal geometry for hydrogen storage of such promising carbon materials as a set of graphene layers and bundles of carbon nanotubes. We demonstrate that the hydrogen storage capacity depends on the geometry of material and discuss the origin of this effect.

Department of Science and Technology (DST) for funding through HySA program, grant number: KP5-I04 (Electrochemical Hydrogen Compression and Separation); National Research Foundation (NRF) of South Africa, grant: 85309.

Paper refers to the construction of procedural simulators for expert systems management devices of rocket and space technology ground infrastructure objects. A classification of courses, which allows to realize the development of skills with both hardware and software components of a diagnostic expert systems. A method of calculating the integrated assessment of the student mastery of the material.

The Vpu protein of HIV-1 antagonizes BST-2 (tetherin), a broad spectrum effector of the innate immune response to viral infection, by an intermolecular interaction that maps genetically to the α-helical transmembrane domains (TMDs) of each protein. Here we utilize NMR spectroscopy to describe key features of the helix-helix pairing that underlies this interaction. The antagonism of BST-2 involves a sequence of three alanines and a tryptophan spaced at four residue intervals within the Vpu TMD helix. Responsiveness to Vpu involves bulky hydrophobic residues in the C-terminal region of the BST-2 TMD helix that likely fit between the alanines on the interactive face of Vpu. These aspects of Vpu and BST-2 form an anti-parallel, lipid-embedded helix-helix interface. Changes in human BST-2 that mimic sequences found in nonhuman primate orthologs unresponsive to Vpu change the tilt angle of the TMD in the lipid bilayer without abrogating its intrinsic ability to interact with Vpu. These data explain the mechanism by which HIV-1 evades a key aspect of innate immunity and the species specificity of Vpu using an anti-parallel helix-helix packing model.

We model the properties and formation of Pt-based catalyst on carbon and non-carbon support, as well as the processes occurring on the PEM Fuel Cell cathode. The target is to self-consistently optimize the catalyst-support system for the mass activity of the oxygen reduction reaction (ORR) in PEM FC. The doping of Pt-alloy catalyst and its interaction with support can dramatically affect the activity and durability of the system. Understanding of the physics and chemistry of this system is crucial for rational design of new catalyst for PEM FC. We use molecular mechanics and molecular dynamics simulations with the Sutton-Chen interaction potentials optimized to model transition metal clusters. The results of calculations agree with experimental data. © 2011 ECS - The Electrochemical Society., 11th Polymer Electrolyte Fuel Cell Symposium, PEFC 11 - 220th ECS Meeting, October 9-14, 2011, Boston, MA, USA

The HIV-1 protein Vpu counteracts the antiviral activity of the innate restriction factor BST-2/tetherin by a mechanism that partly depends on its interaction with β-TrCP, a substrate adaptor for an SCF (Skp-Cullin 1-F box) E3 ubiquitin ligase complex. This suggests that Vpu stimulates the ubiquitination of BST-2 and that this underlies the relief of restriction. Here, we show that Vpu stimulates ubiquitination of BST-2. Mutation of all potential ubiquitination sites in the cytoplasmic domain of BST-2, including lysines, cysteines, serines, and threonines, abrogates Vpu-mediated ubiquitination. However, a serine-threonine-serine sequence specifically mediates the downregulation of BST-2 from the cell surface and the optimal relief of restricted virion release. Serine-threonine ubiquitination of BST-2 is likely part of the mechanism by which Vpu counteracts innate defenses.

BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins. DOI: http://dx.doi.org/10.7554/eLife.02362.001, eLife digest HIV is a retrovirus that attacks the immune system, making the body increasingly susceptible to opportunistic infections and disease and eventually leading to AIDS. While antiretroviral drugs have allowed people with AIDS to live longer, there is no cure or vaccine for HIV. Two types of HIV exist, with HIV-1 being much more common and pathogenic than HIV-2. Like other ‘complex’ retroviruses, the HIV-1 genome contains genes that encode various proteins that allow the virus to disrupt the immune response of the host it is attacking. Viral protein u is a protein encoded by HIV-1 (but not HIV-2) that counteracts an antiviral protein called BST2 in the host. BST2, which is part of the host's innate immune response, prevents newly formed viruses from leaving the surface of infected cells. By counteracting BST2, viral protein u allows the virus to spread in the host more efficiently. Like many proteins, newly produced BST2 is packaged inside structures called vesicles in a part of the cell called the trans-Golgi network, and then sent to its destination. Complexes formed by various proteins make sure that the vesicles take their cargo to their correct destinations within the cell. Two adaptor protein complexes—known as AP1 and AP2—are thought to be involved the transport of BST2. However, it is not known how viral protein u stops BST2 from reaching the cell surface, or how it decreases the amount of BST2 in the cell as a whole. Jia et al. show how viral protein u and BST2 jointly interact with AP1. This interaction leads to the mistrafficking and degradation of BST2 and the counteraction of its antiviral activity. DOI: http://dx.doi.org/10.7554/eLife.02362.002

BST2 (HM1.24; CD317; tetherin) is an interferon-inducible transmembrane protein that restricts the release of several enveloped viruses, including HIV, from infected cells. Before its activity as an antiviral factor was described, BST2 was identified as an inducer of NF-κB activity. Here we show that human BST2 induces NF-κB in a dose-dependent manner. This activity is separable from the restriction of virus release: a YxY sequence in the cytoplasmic domain of BST2 is required for the induction of NF-κB but is dispensable for restriction, whereas the glycosylphosphatidylinositol (GPI) addition site in the protein's ectodomain is required for restriction but is largely dispensable for the induction of NF-κB. Mutations predicted to disrupt the coiled-coil structure of the BST2 ectodomain impaired both signaling and restriction, but disruption of the tetramerization interface differentially affected signaling. The induction of NF-κB by BST2 was impaired by inhibition of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) or by calcium chelation, suggesting potential linkage to the mitogen-activated protein kinase and endoplasmic reticulum (ER) stress response pathways. Consistent with a role for TAK1, BST2 coimmunoprecipitated with TAK1 and the TAK1-associated pseudophosphatase TAB1; these interactions required the YxY sequence in BST2. Moreover, signaling by BST2 was blocked by expression of an IκB-mutant that inhibits the canonical pathway of NF-κB activation. The expression of HIV-1 Vpu inhibited the induction of NF-κB by BST2; this inhibition required Vpu's ability to bind the cellular β-TrCP-E3-ubiquitin ligase complex. The expression of HIV-1 lacking vpu augmented the induction of NF-κB activity by BST2, suggesting that BST2 can act as a virus sensor. This augmentation was also inhibited by Vpu in a β-TrCP-dependent manner. The role of BST2 in the host-pathogen relationship is apparently multifaceted: signaling during the innate immune response, sensing of viral gene expression, and direct restriction of virus release. HIV-1 Vpu counteracts each of these functions.

Human cells respond to infection by retroviruses through the actions of proteins that inhibit the spread of viruses to other cells. One example is bone marrow stromal cell antigen 2 (BST2; also known as tetherin), which is an interferon (IFN)-inducible protein that restricts the release of progeny virions from infected cells. The HIV-1 accessory protein Vpu (viral protein U) causes degradation of BST2, and phosphorylation of Vpu at residues Ser(52) and Ser(56) is required for this function. We report that the host protein SCY1-like protein 2 (SCYL2) mediates the dephosphorylation of Vpu, antagonizing Vpu function and facilitating BST2-dependent restriction of HIV-1 release. SCYL2 reduced the number of virus particles released from cells infected with wild-type HIV-1, but not a strain lacking vpu, in a BST2-dependent manner. SCYL2 stimulated the dephosphorylation of Vpu on Ser(52) and Ser(56) by recruiting protein phosphatase 2A (PP2A) to Vpu. Conversely, depletion of SCYL2 resulted in enhanced phosphorylation of Vpu and increased viral particle release. Moreover, SCYL2 was produced in response to type I IFN and contributed to IFN-mediated viral restriction. Together, these results suggest that SCYL2 serves as a regulatory factor for Vpu, reducing the extent of Vpu phosphorylation and consequently enhancing BST2-mediated viral restriction.

The HIV-1 accessory protein Nef is well known for its manipulation of host cell endosomal trafficking. By linking transmembrane proteins to endosomal coats, Nef removes them from the surface of infected cells. Modulation of MHC proteins leads to viral evasion of cellular adaptive immunity, whereas modulation of receptors for the HIV envelope glycoprotein, including CD4, enhances viral infectivity. The other HIV-1 accessory proteins, Vif, Vpr and Vpu, share a mechanism of action distinct from Nef in that each interacts with a multi-subunit ubiquitin ligase complex to target cellular proteins for proteosomal degradation. However, newly uncovered functions and mechanistic aspects of Vpu likely involve endosomal trafficking: these include counteraction of the innate antiviral activity of the cellular transmembrane protein BST-2 (tetherin), as well as the removal of the lipid-antigen presenting protein CD1d and the natural killer cell ligand NTB-A from the cell surface. This review focuses on how Nef and Vpu interfere with normal intracellular membrane trafficking to facilitate the spread and virulence of HIV-1.

Pathogenic microorganisms encode proteins that antagonize specific aspects of innate or adaptive immunity. Just as the study of the HIV-1 accessory protein Vif led to the identification of cellular cytidine deaminases as host defense proteins, the study of HIV-1 Vpu recently led to the discovery of the interferon-induced transmembrane protein BST-2 (CD317; tetherin) as a novel component of the innate defense against enveloped viruses. BST-2 is an unusually structured protein that restricts the release of fully formed progeny virions from infected cells, presumably by a direct retention mechanism that is independent of any viral protein target. Its spectrum of activity includes at least four virus families: retroviruses, filoviruses, arenaviruses, and herpesviruses. Viral antagonists of BST-2 include HIV-1 Vpu, HIV-2 and SIV Env, SIV Nef, the Ebola envelope glycoprotein, and the K5 protein of KSHV. The mechanisms of antagonism are diverse and currently include viral cooption of cellular endosomal trafficking and protein degradation pathways, including those mediated by ubiquitination. Orthologs of human BST-2 are present in mammals. Primate BST-2 proteins are differentially sensitive to antagonism by lentiviral Vpu and Nef proteins, suggesting that BST-2 has subjected lentiviruses to evolutionary pressure and presents barriers to cross-species transmission. BST-2 functions not only as an effector of the interferon-induced antiviral response but also as a negative feedback regulator of interferon production by plasmacytoid dendritic cells. Future work will focus on the role and regulation of BST-2 during the innate response to viral infection, on the mechanisms of restriction and of antagonism by viral gene products, and on the role of BST-2 in primate lentiviral evolution. The augmentation of BST-2 activity and the inhibition of virally encoded antagonists, in particular Vpu, represent new approaches to the prevention and treatment of HIV-1 infection.

Using density functional theory we investigate a novel carbon allotrope 'SqC': a square planar material that can be more than tetracoordinated. Carbon atoms in this 2D square Bravais lattice form an unusual five-center four-electron bond with neighboring four carbon atoms (tetracoordination). Such an electron-deficient bonding leaves an empty orbital which enables penta- or hexa-coordinated carbon atom. Indeed, our simulations demonstrate such penta- and hexa-coordinated configurations upon partial and complete hydrogenation, respectively. Surprisingly, in all the forms SqC shows the metallic character. SqC has the binding energy of 6.7 eV and it also satisfies the Born stability criteria. Yet our phonon calculations show that it may only be considered as quasi-stable.

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