HIV-1-specific monoclonal antibodies (mAbs) with extraordinary potency and breadth have recently been described. In humanized mice, combinations of mAbs have been shown to suppress viremia, but the therapeutic potential of these mAbs has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific mAbs, as well as the single glycan-dependent mAb PGT121, resulted in a rapid and precipitous decline of plasma viremia to undetectable levels in rhesus monkeys chronically infected with the pathogenic virus SHIV-SF162P3. A single mAb infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa, and lymph nodes without the development of viral resistance. Moreover, following mAb administration, host Gag-specific T lymphocyte responses exhibited improved functionality. Virus rebounded in the majority of animals after a median of 56 days when serum mAb titers had declined to undetectable levels, although a subset of animals maintained long-term virologic control in the absence of further mAb infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific mAbs in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of mAb therapy for HIV-1 in humans.

Systems vaccinology of the BNT162b2 mRNA vaccine in humans P ra bh u S. A ru na ch al am , M ad el ei ne K. D.

Stable BioNetGen releases (Linux, Mac OS/X and Windows), with documentation, are available at http://bionetgen.org Source code is available at http://github.com/RuleWorld/bionetgen CONTACT: bionetgen.help@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.

Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.is a process in which small amounts of allergen are given over time to the allergic individual until they can safely tolerate high amounts of allergen with no signs of clinical symptoms (1-9). In the regimen of oral IT for peanut-allergic patients (identified by an allergic reaction during a standardized blinded food challenge to peanut), small amounts of peanut flour protein are ingested and escalated to a servings-worth of peanut protein (4 g of peanut protein) over a period of 2-3 y (6-7). Most patients require continuous frequent (e.g., daily) exposure to such therapy for beneficial clinical outcomes. Mechanistic studies of oral IT to food allergens, although limited to date, show that plasma markers such as IgE and IgG4 immunoglobulins, skin test markers, component testing, and basophil activation tests are only weakly predictive of long-term clinical success (10-16). T cells are critical upstream regulators of allergic sensitization that are required to help B cells to synthesize IgE/IgG4 immunoglobulins, which then can activate or inhibit basophils and mast cells (10-17). Moreover, successful IT is associated with the development of regulatory T cells (Tregs) that are thought to dampen allergic reactivity to offending allergens (7). We therefore focused on finding T-cell markers of immune tolerance that could be detected early in the peripheral blood during IT. CD4+ T cells can be relatively long-lived (compared with plasma proteins and basophils) and changes detected early in populations of T cells could perhaps predict longer-lasting successful IT. For example, in one of the first studies in peanut allergen IT to withdraw therapy for more than 10 wk, we previously showed that despite negative skin tests to peanut, and high IgG4/low specific IgE levels to peanut, and decreased basophil reactivity to the allergen, some patients who withdrew from therapy for 3-6 mo were still reactive upon rechallenge with peanut (7...

Although cytokine-dependent dynamics of nuclear factor κB (NF-κB) are known to encode information that regulates cell fate decisions, it is unclear whether single-cell responses are switch-like or encode more information about cytokine dose. Here, we measure the dynamic subcellular localization of NF-κB in response to a range of tumor necrosis factor (TNF) stimulation conditions to determine the prevailing mechanism of single-cell dose discrimination. Using an information theory formalism that accounts for signaling dynamics and non-responsive cell subpopulations, we find that the information transmission capacity of single cells exceeds that predicted from a switch-like response. Instead, we observe that NF-κB dynamics within single cells contain sufficient information to encode multiple, TNF-dependent cellular states, and have an activation threshold that varies across the population. By comparing single-cell responses to an internal, experimentally observed reference, we demonstrate that cells can grade responses to TNF across several orders of magnitude in concentration. This suggests that cells contain additional control points to fine-tune their cytokine responses beyond the decision to activate.

Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-β, regulatory T cells and IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of peripheral blood from patients with TB, immunoregulatory trends mirror those identified by granuloma imaging. Notably, PD-L1 expression is associated with progression to active TB and treatment response. These data indicate that in TB granulomas, there are local spatially coordinated immunoregulatory programs with systemic manifestations that define active TB.

Background Basophil activation tests (BATs) have promise for research and for clinical monitoring of subjects with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies. Objective To attempt to establish a BAT protocol that would permit analysis of blood within 24 hours of obtaining the sample. Methods Blood from 46 healthy donors and 120 peanut allergic patients was collected into ethylenediaminetetraacetic acid (EDTA) or heparin tubes, and samples were stored at 4°C or room temperature for 4 or 24 hours before performing BATs. Results Stimulation with anti-Immunoglobulin E (anti-IgE) or interleukin-3 (IL-3) resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4°C, and analyzed 24 hours after sample collection. However, a CD63hi population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and for identification of a population of CD63hi basophils, whether the specimens were analyzed by conventional flow cytometry or by Cytometry by Time-of-Flight mass spectrometry (CyTOF), and such tests could be performed after blood was stored for 24 hours at 4°C. Conclusion BATs to measure upregulation of basophil CD203c and induction of a CD63hi basophil population can be conducted using blood obtained in heparin tubes and stored at 4°C for 24 hours.

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