Structure of FcRY, an avian immunoglobulin receptor related to mammalian mannose receptors, and its complex with IgY

Fc receptors transport maternal antibodies across epithelial cell barriers to passively immunize newborns. FcRY, the functional counterpart of mammalian FcRn (a major histocompatibility complex homolog), transfers IgY across the avian yolk sac, and represents a new class of Fc receptor related to the mammalian mannose receptor family. FcRY and FcRn bind immunoglobulins at pH ≤6.5, but not pH ≥7, allowing receptor–ligand association inside intracellular vesicles and release at the pH of blood. We obtained structures of monomeric and dimeric FcRY and an FcRY–IgY complex and explored FcRY's pH-dependent binding mechanism using electron cryomicroscopy (cryoEM) and small-angle X-ray scattering. The cryoEM structure of FcRY at pH 6 revealed a compact double-ring “head,” in which the N-terminal cysteine-rich and fibronectin II domains were folded back to contact C-type lectin-like domains 1–6, and a “tail” comprising C-type lectin-like domains 7–8. Conformational changes at pH 8 created a more elongated structure that cannot bind IgY. CryoEM reconstruction of FcRY dimers at pH 6 and small-angle X-ray scattering analysis at both pH values confirmed both structures. The cryoEM structure of the FcRY–IgY revealed symmetric binding of two FcRY heads to the dimeric FcY, each head contacting the CH4 domain of one FcY chain. FcRY shares structural properties with mannose receptor family members, including a head and tail domain organization, multimerization that may regulate ligand binding, and pH-dependent conformational changes. Our results facilitate understanding of immune recognition by the structurally related mannose receptor family and comparison of diverse methods of Ig transport across evolution

Interrupting Antiretroviral Treatment in HIV Cure Research: Scientific and Ethical Considerations

Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions. The lack of definitive assays for measuring viral reservoirs not only makes research on HIV remission or cure challenging, it also affects the ability to assess risks from ATIs themselves. In spite of these challenges, basic ethical criteria can be met with careful study design and close monitoring. In this brief report we outline ethical standards for HIV cure research involving ATIs. These criteria should be revisited as the science evolves

The Chicken Yolk Sac IgY Receptor, a Mammalian Mannose Receptor Family Member, Transcytoses IgY across Polarized Epithelial Cells

In mammals the transfer of passive immunity from mother to young is mediated by the MHC-related receptor FcRn, which transports maternal IgG across epithelial cell barriers. In birds, maternal IgY in egg yolk is transferred across the yolk sac to passively immunize chicks during gestation and early independent life. The chicken yolk sac IgY receptor (FcRY) is the ortholog of the mammalian phospholipase A2 receptor, a mannose receptor family member, rather than an FcRn or MHC homolog. FcRn and FcRY both exhibit ligand binding at the acidic pH of endosomes and ligand release at the slightly basic pH of blood. Here we show that FcRY expressed in polarized mammalian epithelial cells functioned in endocytosis, bidirectional transcytosis, and recycling of chicken FcY/IgY. Confocal immunofluorescence studies demonstrated that IgY binding and endocytosis occurred at acidic but not basic pH, mimicking pH-dependent uptake of IgG by FcRn. Colocalization studies showed FcRY-mediated internalization via clathrin-coated pits and transport involving early and recycling endosomes. Disruption of microtubules partially inhibited apical-to-basolateral and basolateral-to-apical transcytosis, but not recycling, suggesting the use of different trafficking machinery. Our results represent the first cell biological evidence of functional equivalence between FcRY and FcRn and provide an intriguing example of how evolution can give rise to systems in which similar biological requirements in different species are satisfied utilizing distinct protein folds

Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy

Background. Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells. Methods. We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to 350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results. Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS- 936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions. In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single lowdose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants

Telomerase Inhibition Targets Clonogenic Multiple Myeloma Cells through Telomere Length-Dependent and Independent Mechanisms

Plasma cells constitute the majority of tumor cells in multiple myeloma (MM) but lack the potential for sustained clonogenic growth. In contrast, clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC). These tumor initiating B cells also share functional features with normal stem cells such as drug resistance and self-renewal potential. Therefore, the cellular processes that regulate normal stem cells may serve as therapeutic targets in MM. Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC. Moreover, we carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities.Human MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. In addition to these relatively long-term effects, 72 hours of imetelstat treatment inhibited clonogenic growth that was associated with MM CSC differentiation based on expression of the plasma cell antigen CD138 and the stem cell marker aldehyde dehydrogenase. Short-term treatment of MM CSC also decreased the expression of genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1) as revealed by quantitative real-time PCR.Telomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms

Polymorphisms in the Estrogen Receptor 1 and Vitamin C and Matrix Metalloproteinase Gene Families Are Associated with Susceptibility to Lymphoma

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. CONCLUSIONS/SIGNIFICANCE: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation

Recommendations for analytical antiretroviral treatment interruptions in HIV research trials: report of a consensus meeting

Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research