HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection

Magnetic-field symmetries of mesoscopic nonlinear conductance

We examine contributions to the dc-current of mesoscopic samples which are non-linear in applied voltage. In the presence of a magnetic field, the current can be decomposed into components which are odd (antisymmetric) and even (symmetric) under flux reversal. For a two-terminal chaotic cavity, these components turn out to be very sensitive to the strength of the Coulomb interaction and the asymmetry of the contact conductances. For both two- and multi-terminal quantum dots we discuss correlations of current non-linearity in voltage measured at different magnetic fields and temperatures.Comment: 9 pages, 4 figure

SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition.

Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted

Negotiating the inhuman: Bakhtin, materiality and the instrumentalization of climate change

The article argues that the work of literary theorist Mikhail M. Bakhtin presents a starting point for thinking about the instrumentalization of climate change. Bakhtin’s conceptualization of human–world relationships, encapsulated in the concept of ‘cosmic terror’, places a strong focus on our perception of the ‘inhuman’. Suggesting a link between the perceived alienness and instability of the world and in the exploitation of the resulting fear of change by political and religious forces, Bakhtin asserts that the latter can only be resisted if our desire for a false stability in the world is overcome. The key to this overcoming of fear, for him, lies in recognizing and confronting the worldly relations of the human body. This consciousness represents the beginning of one’s ‘deautomatization’ from following established patterns of reactions to predicted or real changes. In the vein of several theorists and artists of his time who explored similar ‘deautomatization’ strategies – examples include Shklovsky’s ‘ostranenie’, Brecht’s ‘Verfremdung’, Artaud’s emotional ‘cruelty’ and Bataille’s ‘base materialism’ – Bakhtin proposes a more playful and widely accessible experimentation to deconstruct our ‘habitual picture of the world’. Experimentation is envisioned to take place across the material and the textual to increase possibilities for action. Through engaging with Bakhtin’s ideas, this article seeks to draw attention to relations between the imagination of the world and political agency, and the need to include these relations in our own experiments with creating climate change awareness

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART

Phenotypic plasticity of nest-mate recognition cues in formica exsecta ants

It is well established that many ant species have evolved qualitatively distinct species-specific chemical profile that are stable overlarge geographical distances. Within these species profiles quantitative variations in the chemical profile allows distinct colony-specific odours to arise (chemotypes) that are shared by all colony members. This help maintains social cohesion, includingdefence of their colonies against all intruders, including con-specifics. How these colony -level chemotypes are maintainedamong nest-mates has long been debated. The two main theories are; each ant is able to biochemically adjust its chemical profileto‘match’that of its nest-mates and or the queen, or all nest-mates share their individually generated chemical profile viatrophollaxis resulting in an average nest-mate profile. This‘mixing’idea is better known as theGestaltmodel. Unfortunately,it has been very difficult to experimentally test these two ideas in a single experimental design. However, it is now possible usingthe antFormica exsectabecause the compounds used in nest-mate recognition compounds are known. We demonstrate thatworkers adjust their profile to‘match’the dominant chemical profile within that colony, hence maintaining the colony-specificchemotype and indicates that a‘gestalt’mechanism, i.e. profile mixing, plays no or only a minor role

Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera

Sedimentary Ways

This paper is a thought experiment to attune to the geo-physical and geo-political materialities of sediment, a terra-aqueous substance produced when the earth's continental surfaces intra-act with the atmosphere and are chemically transformed by it. The paper is framed by questions of how to engage more closely with the dynamics of earth systems and of how social and political agency emerges alongside earth forces. Sediment is important to such questions because it is the mechanism by which the earth recycles itself and is thick with the climatological and geological histories that have conditioned the possibility of life on the planet. While acknowledging the import of Deleuze and Guattari's metaphysics to such questions, the paper takes a material approach to them. It is based on field work in Bangladesh, but also traverses a range of scientific, historical and theoretical literature. It is arranged in four sections that loosely correspond to the sedimentary cycle. It follows sediment from chemical processes on rock surfaces in the Himalayas, to its lively travels in monsoonal rivers across flood plains to its eventual deposition and subterranean diagenesis. In each section, the paper discusses the material processes at work, their socio-political enmeshments and the theoretical implications of these intra-actions. The paper concludes that sediment serves as a reminder not only of close entanglements of geo-physical and geo-political becomings, but also of the profound indifference of earth systems to human affairs, and asks what this might mean for the re-imagination of politics

Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy

The latent viral reservoir formed by HIV-1, mainly in CD4 + T cells, is responsible for the failure of antiretroviral therapy (ART) to achieve a complete elimination of the virus in infected individuals. We previously determined that CD4 + T cells from individuals with chronic myeloid leukemia (CML) on treatment with dasatinib are resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral effect is the preservation of SAMHD1 activity. In this study, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIV-infected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML (1:65,000), three male individuals were recruited in Spain and Germany. These individuals had been on treatment with standard ART and dasatinib for median 1.3 years (IQR 1.3-5.3 years). Reservoir size and composition in PBMCs from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells was reduced more than 5-fold in these individuals. The reactivation of proviruses from these cells was reduced more than 4-fold and, upon activation, SAMHD1 phosphorylation was reduced 40-fold. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. Therefore, treatment of HIV-infected individuals with dasatinib as adjuvant of ART could disturb the reservoir reactivation and reseeding, which might have a beneficial impact to reduce its size

Is bisexuality invisible? A review of sexualities scholarship 1970–2015

This article provides a review of sexualities scholarship within the social sciences between 1970 and 2015. It takes an innovative approach by focusing on the way in which bisexuality is addressed in this body of literature. The article reveals the marginalisation, under-representation and invisibility of bisexuality within and across the social sciences in relation to both bisexual experience and identity. Reasons for this varied across the different eras, including the heterosexist nature of the literature, the impact of gay and lesbian-focused identity politics, and queer deconstructionism. In addition, patterns of bisexual erasure and invisibility were uneven, with some scholarship taking inclusive approaches or criticising prejudice against bisexuality. The initial findings of the review were enriched by critical commentary from key relevant sociologists and political scientists. The article concludes that future sexualities scholarship could be enhanced by greater consideration of bisexuality