Biology subjects

Shaw, G. M.

Publications and source records attributed to Shaw, G. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatial Logic and Evolutionary Innovation in Human Placentation

Human pregnancy unfolds in a unique mosaic tissue context. Embryonic/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker NID2, which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific NID2 promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower NID2 expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts in vitro. Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal-fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.

genomics↗

bioRxiv2026

Asymmetric Boost Responses to an HIV-1 Vaccine: Boost-site Controls Secondary B-cell Fates

Induction of broadly neutralizing antibody (bnAb) responses remains a central challenge to designing efficacious HIV vaccines. Lineage design strategies, in which bnAb precursors are guided via iterative immunizations to their mature forms, depend on high levels of somatic mutation and the recall of antigen-specific B cells. Recent studies have identified spatial context as an important determinant of boosting efficacy, but the application of this to HIV vaccines and the underlying mechanisms are incompletely understood. Here, using mice harboring a V3-glycan bnAb lineage precursor knock-in combined with lineage-tracing and single-cell analyses, we show that persistent germinal centers (GCs) support continued affinity maturation of founder clones and ipsilateral boosting preferentially engages these lineages in secondary GCs. In contrast, contralateral boosting predominantly recruits naive B cells and memory B cells not directed towards the immunizing antigen. The few memory cells recruited at this site were biased towards a plasma cell fate. Finally, we identify disfavored mutational trajectories within the V3-glycan bnAb lineage, revealing intrinsic constraints on bnAb lineage evolution.

immunology↗

bioRxiv2026

Rapid vaccine induction of macaque HIV-1 V2 Apex broadly neutralizing antibodies with immunogenetic signatures that are potentially translatable to humans

Due to the complex biology of HIV-1 broadly neutralizing antibodies (bnAbs), HIV-1 vaccines must target unmutated germline precursor antibodies with B cell receptors that have the appropriate specificity and genetic features to develop neutralization breadth. Previous work has shown that immunization or infection in macaques primes unmutated precursor antibodies that target the broadly neutralizing epitope composed of the second variable region and proximal glycans (termed V2-apex site) of HIV-1 envelope (Env). Macaque V2-apex bnAb precursors elicited thus far have homogeneous usage of the second reading frame of a diversity (D) gene found only in macaques, calling into question whether HIV-1 Env immunogens can elicit only this canonical, macaque-specific V2-apex antibody response, limiting human vaccination success. Here, we show that vaccination of rhesus macaques with Env conjugated to a ferritin nanoparticle (OPT4-scNP) rapidly elicited V2-apex bnAbs with distinct D gene segment usage and motifs that are not restricted only to macaques. After two priming immunizations, V2-apex antibodies with non-canonical HCDR3s exhibited greater neutralization potency and breadth than V2-apex antibodies with previously observed HCDR3 motifs. Following sequential boosting immunizations, a V2-apex bnAb lineage with a novel HCDR3-encoded EDGED motif increased its neutralization breadth, including neutralization of viral isolates bearing the N130 glycan, which shields the V2-apex from recognition. High-resolution structures of two members of this V2-apex bnAb lineage, called DH2050, defined a novel binding mode in which it used its EDGED motif to contact the C-strand peptide and the N160 glycan within the V2-apex site. Altogether, we define a novel bnAb binding mode to the V2 Apex and demonstrate that HIV-1 Env sequential vaccination elicits V2-apex bnAbs with immunogenetic signatures that are potentially translatable to the human immune system.

immunology↗

bioRxiv2026

Early clonal dominance at priming sets the trajectory for broad HIV serum neutralization

Inducing broadly neutralizing antibodies (bnAbs) remains a central challenge in HIV vaccine development 1-3. Germline-targeting immunogens are designed to activate rare bnAb precursor B cell lineages 4-12, yet the relationships between priming efficiency, clonal dominance, and downstream serum neutralization remain poorly defined. We recently demonstrated that vaccination with an engineered V2-apex germline-targeting trimer Q23-APEX-GT2 successfully recruits and activates rare long-CDRH3 B cell precursors in outbred macaques 13. Here, we dissect the immunological mechanisms governing bnAb precursor priming and early B cell expansion and define clonal features that drive progression to serum neutralization breadth. Our antigen-specific B cell analyses showed that Q23-APEX-GT2 consistently engaged long-CDRH3 precursors, although priming efficiency varied across animals. Longitudinal deep lineage tracing across lymph node and blood compartments revealed that early recruitment of multiple diverse long-CDRH3 lineages, followed by preferential expansion and dominance of one or two clones, strongly predicted serum neutralization potency. Subsequent CAP256.SU SHIV infection efficiently recalled vaccine-seeded clones, accelerated affinity maturation, and drove broad heterologous neutralization in most animals. Notably, one macaque with diverse and expanded V2-apex lineages rapidly achieved [~]70% serum neutralization breadth. Importantly, longitudinal tracing revealed that bona fide bnAbs can emerge from vaccine-primed precursors, while also uncovering "born-wrong" bnAb-like lineages that expand yet remain non-neutralizing, despite structurally validated recognition of the V2-apex bnAb site. Together, these findings establish priming efficiency coupled with early clonal dominance as key determinants of serum bnAb induction and provide a mechanistic framework to guide rational HIV vaccine design.

immunology↗

bioRxiv2026

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

immunology↗

bioRxiv2026

Functional Convergence of Genetically Diverse B-Cell Receptors in Simian-HIV Infected Rhesus Macaques

Germline-targeting or lineage-design vaccine strategies are being used to induce HIV broadly neutralizing antibody (bnAb) responses. These strategies assume that genetically diverse individuals respond similarly to the same immunogen by mobilizing comparable germline precursors, although outcomes vary across bnAb epitopes. Here we explored this premise using a simian-HIV infection model in rhesus macaques. Antigen-unbiased Env- reactive B-cell populations were profiled, followed by systematic analysis of antibody function and B-cell receptor (BCR) genetics. We find that while global Env-reactive B-cell response profiles and antibody functional properties are similar across individuals, underlying BCR genetics are diverse, particularly among non-bnAbs. These results indicate that functional convergence of Env-reactive antibody responses does not necessarily require genetic convergence and suggest that specific germline-targeting may not be an absolute prerequisite for successful vaccine design. These findings support an epitope-focused framework in which bnAb epitopes are engineered to enhance population-level immunogenicity, with potential applicability to other challenging pathogens.

immunology↗

bioRxiv2025

An integrated workflow for structural virology with a 100 keV electron microscope

Cryo-EM has revolutionized structural biology, especially for flexible and heterogeneous samples, although access to high end microscopes that enable these studies remains a bottleneck. While 300 keV microscopes have been the go-to for high-resolution structural determination, they are expensive and restricted to institutional and national facilities needing specialized expertise, with access falling far short of the demand. Here, we present the user-managed operation of a cheaper 100 keV electron microscope within a structural biology laboratory enabling close integration with protein production, biochemical and biophysical studies. We provide details and considerations for the installation of the microscope, its day-to-day maintenance, and operations. Using virus surface glycoproteins as case studies, we illustrate the workflow from grid screening, data collection, and data processing, and provide examples of data quality. This user-administered setup provides a training platform for researchers at all levels, with beginners in cryo-EM achieving proficiency to independently operate the microscope within a month of regular use and training. We have demonstrated routine high-quality low-resolution reconstructions using a Ceta CMOS camera and high-resolution reconstructions enabling building of atomic models using a Falcon C direct detector. While there are several examples of facilities that manage cryo-EM and individual laboratories leveraging cryo-EM, we provide here the first demonstration of a modern group independently doing both successfully, something that has been talked about frequently but rarely seen.

biochemistry↗

bioRxiv2025

Systemic immune dysregulation in hypertensive disorders of pregnancy persists years after delivery

BackgroundHypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, are associated with an increased risk of cardiovascular disease (CVD) later in life. Mechanisms that link HDP to CVD, however, remain unclear. MethodsWe used a high-dimensional single-cell mass cytometry approach to profile the distribution and functional responses of maternal immune cells in three separate groups of HDP cases and normotensive controls, sampled antepartum, postpartum, and several years postpartum (midlife). We used multivariable sparse modeling to distinguish HDP cases from controls. ResultsWe accurately distinguished HDP cases from controls at all three study timepoints, with area under the receiver operator characteristic (AUROC) curve values of 0.814 for the antepartum group, 0.757 for the postpartum group, and 0.692 for the midlife group. Distinct immune signatures for each model underscore the dynamic dysregulation of the immune system throughout life. In addition, we identified a persistent immune dysregulation signal among HDP cases at all three timepoints, characterized by increased B cell frequency and decreased pSTAT3 response upon cytokine stimulation in classical monocytes. ConclusionsPersistent immune dysregulation among women with a history of an HDP may contribute to elevated long-term risk of CVD development.

immunology↗

bioRxiv2025

Structure-guided design of native-like HIV Env Single Chain Trimers for enhanced stability, immunogenicity, and versatile vaccine delivery

Stabilizing the HIV envelope (Env) trimer in its native prefusion conformation is key to eliciting broadly neutralizing antibodies (bnAbs). We present a generalizable single-chain trimer-(SCT) design platform that enables the production of stable, native-like Env trimers across diverse HIV strains. Using a structure-guided approach, we developed CAP256.SU-SCT9, based on a CAP256.SU Env shown to induce V2-apex bnAbs in humans and rhesus macaques. CAP256.SU-SCT9 trimer exhibited native-like structure, bnAb-specific antigenicity, authentic glycosylation, and compatibility with nucleic acid and nanoparticle delivery. We extended this design strategy to a panel of HIV Envs representing global diversity, and immunogens known to initiate bnAb responses in humans. Structural analyses confirmed that SCTs consistently maintained prefusion-closed conformations, favorable glycan profiles, strong binding to trimer-specific bnAbs, and low reactivity with non-neutralizing antibodies. These findings establish SCT as a versatile platform for HIV trimer immunogen design, with potential to support next-generation vaccines aimed at eliciting protective bnAb responses.

immunology↗

bioRxiv2025

Single-cell-level digital twins for preterm birth prevention strategies

Digital twin models can accelerate therapeutic development by enabling low-risk testing of candidate interventions. In preterm labor (PTL), a major pregnancy complication where clinical trials face unique ethical and financial barriers, digital twins are especially valuable for evaluating new therapies targeting immune dysfunctions driving PTL. Yet, current models lack single-cell resolution, limiting detection of cell-type-specific mechanisms, off-target effects, and the design of personalized interventions. We present Simulated Immunome Modeling of Clinical Outcomes (SIMCO), a single-cell-level digital twin framework that models immunomodulatory treatment effects on the timing of labor using immunome-wide, single-cell simulations. SIMCOs digital twins are trained and validated on a newly generated mass cytometry atlas of the pregnant immunome exposed to nine candidate drugs preselected for PTL prevention. Applying SIMCO to an independent cohort of pregnant individuals, we simulate treatment effects on gestational length, screening for candidate drugs that delay labor timing and providing system-level mechanistic insight for each drug candidate. Tetrahydrofolate, maprotiline, and the combination of aspirin and lansoprazole emerged as top candidates for PTL prevention, delaying labor onset primarily through enhanced mTOR signaling in innate immune cells and attenuated JAK/STAT signaling in naive CD4 T cells. The codebase is available at https://github.com/ofondeur/SIMCO/.

immunology↗

bioRxiv2025

Rapid elicitation of a new class of neutralizing N332-glycan independent V3-glycan antibodies against HIV-1 in nonhuman primates.

Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env-immunogen that induces a new class of neutralizing N332-glycan-independent antibodies to the conserved V3-glycan epitope of Env after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human N332-glycan-dependent (Type-I) V3-glycan bNAbs but also of a first-of-its-class N332-glycan-independent (Type-II) V3-glycan bNAb. A single immunization elicits neutralizing serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. EMPEM analysis of serum antibodies, antibody cloning and cryo-EM analysis reveal that WIN332 elicits N332-glycan-independent antibodies with remarkable sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.

immunology↗

bioRxiv2025

Rapid acquisition of HIV-1 neutralization breadth in a rhesus V2 apex germline antibody mouse model after a single bolus immunization

Current vaccine strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multi-boost immunization regimens. In rhesus macaques, SHIV infection has been observed to rapidly drive the development of some classes of bnAbs that share structural similarities with those in humans. Here, we generated a knockin mouse model with B cells bearing the unmutated common ancestor (UCA) of the V2 apex-targeted bnAb lineage, V033-a. A single immunization of mice with a germline-targeting native-like trimer was sufficient to recapitulate the ontogeny of the mature rhesus bnAb in knockin mice--including rare, disfavored somatic mutations--leading to the induction of antibodies that exhibited potent neutralization against both autologous and heterologous tier 2 viruses. A boost with Env escape mutant trimers further improved breadth and potency, and cryo-EM structure revealed the structural basis for heterologous neutralization breadth. Non-human primate and mouse models can thus combine with structure to serve as a platform for identifying and confirming immunogens that streamline HIV-vaccination regimens.

immunology↗

bioRxiv2024

Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryo-EM structure of RHA10 with HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting glycan deletions in infecting SHIVs could consistently induce CD4bs bNAbs. To test this, we constructed SHIV.CH505.D3 with CD4bs-proximal glycan deletions. Infection of 10 macaques resulted in accelerated CD4bs bNAb responses in 8, compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and thus serve as a model for HIV vaccine design. HighlightsO_LIOut of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbs C_LIO_LICD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potency C_LIO_LITransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb induction C_LIO_LIA novel SHIV with CD4bs-proximal glycan holes and enhanced CD4bs antigenicity immunofocused B cell responses to the CD4bs and elicited cross-clade neutralizing responses in 80% of macaques C_LI

microbiology↗

bioRxiv2024

Deep Mining of the Human Antibody Repertoire Identifies Frequent and Immunogenetically Diverse CDRH3 Topologies Targetable by Vaccination

Germline targeting vaccination strategies against highly variable pathogens such as HIV aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex axe-like CDRH3s in the human repertoire and developing new immunogens capable of engaging them. We determined the frequency and diversity of axe-like CDHR3s in healthy human donors using a series of structural informatics approaches, finding these precursors in nearly 90% of donors. Axe-targeting immunogens based on the HIV Env Q23.17 bound axe-like precursors in cryo-EM structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques infected with a germline-targeted simian-human immunodeficiency virus. These results illustrate a new structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies. Significance StatementMany broadly neutralizing antibodies (bnAbs) utilize modes of epitope recognition dominated by the antibody complementarity determining region 3 (CDRH3). The CDRH3 is the most diverse part of the antibody, posing a challenge for germline targeting vaccine designs that aim to elicit antibodies with particular immunogenetic features. Vaccine design strategies that accommodate CDRH3 variability are therefore needed. Many HIV Env V2 apex bnAbs share "axe-like" CDRH3 microfolds that arise from diverse immunogenetic origins. Here we determined the frequency in humans of B cells with such CDRH3 topologies and designed immunogens to engage their precursors. This work opens a path toward vaccines that engage specific structural classes of B cells, thereby advancing the rational design of immunogens for HIV and other pathogens.

immunology↗

bioRxiv2024

Neutralizing antibodies elicited in sequentially immunized macaques recognize V3 residues on altered conformations of HIV-1 Env trimer

Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers. Highlights- Sequential immunization regimen elicits V3 antibodies targeting non-closed Envs - Cryo-EM structures reveal recognition of multiple Env conformational states - Neutralization by elicited antibody does not require antibody-virus preincubation Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/605918v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6210b1org.highwire.dtl.DTLVardef@35f683org.highwire.dtl.DTLVardef@cb2d3corg.highwire.dtl.DTLVardef@106e066_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition. HighlightsO_LIIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaques C_LIO_LICryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognition C_LIO_LIAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame two C_LIO_LIThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodies C_LIO_LIStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition mode C_LIO_LIPropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naive rhesus repertoire C_LIO_LIDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity C_LI

immunology↗

bioRxiv2024

Comparative Analysis of Within-Host Dynamics of Acute Infection and Viral Rebound Dynamics in Postnatally SHIV-Infected ART-Treated Infant Rhesus Macaques

Viral dynamics of acute HIV infection and HIV rebound following suspension of antiretroviral therapy may be qualitatively similar but must differ given, for one, development of adaptive immune responses. Understanding the differences of acute HIV infection and viral rebound dynamics in pediatric populations may provide insights into the mechanisms of viral control with potential implications for vaccine design and the development of effective targeted therapeutics for infants and children. Mathematical models have been a crucial tool to elucidate the complex processes driving viral infections within the host. Traditionally, acute HIV infection has been modeled with a standard model of viral dynamics initially developed to explore viral decay during treatment, while viral rebound has necessitated extensions of that standard model to incorporate explicit immune responses. Previous efforts to fit these models to viral load data have underscored differences between the two infection stages, such as increased viral clearance rate and increased death rate of infected cells during rebound. However, these findings have been predicated on viral load measurements from disparate adult individuals. In this study, we aim to bridge this gap, in infants, by comparing the dynamics of acute infection and viral rebound within the same individuals by leveraging an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Ten infant Rhesus macaques (RMs) orally challenged with SHIV.C.CH505 375H dCT and given ART at 8 weeks post-infection. These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. We use the HIV standard viral dynamics model fitted to viral load measurements in a nonlinear mixed effects framework. We find that the primary difference between acute infection and rebound is the increased death rate of infected cells during rebound. We use these findings to generate hypotheses on the effects of adaptive immune responses. We leverage these findings to formulate hypotheses to elucidate the observed results and provide arguments to support the notion that delayed viral rebound is characterized by a stronger CD8+ T cell response.

immunology↗

bioRxiv2024

A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface

The placenta, the first organ to functionally mature, undergoes disordered development in many pregnancy complications. Molecular investigations have been hampered by the extreme cellular heterogeneity of the placenta, and this complexity is further exaggerated at the maternal-fetal interface where maternal and fetal cells co-mingle. We generated the paired single nucleus epigenomes and transcriptome for each of [~]200,000 cells at the human maternal-fetal interface from early pregnancy to term. These data identified cell-type-specific transcriptional regulatory programs and uncovered key transcription factors driving the lineage differentiation of placental cytotrophoblasts. Integrating spatial single cell proteomics profiling, we localized the observed cell types in situ, and characterized the dynamic stages and distinct features of endothelial cells of maternal spiral arteries remodeled by extravillous cytotrophoblasts. Integrative analyses of the single cell data across gestation enabled fine-mapping of the developmental trajectories of cytotrophoblasts and decidual stromal cells, and defining the signature molecular profiles of known and novel cell (sub)types. To demonstrate clinical value, we integrated the reference single cell data with large-scale population genomes from pregnancy complications and identified the most vulnerable maternal and fetal cell types in preeclampsia, preterm birth, and miscarriage. This study presents the most comprehensive placental and decidual single cell resource across gestation to date, reveals new insights into the drivers of normal human placentation, and uncovers the cellular basis of dysfunction associated with common pregnancy complications.

genomics↗