About

Beatrice H. Hahn, M.D., is a Professor of Medicine (Hematology-Oncology) at the Perelman School of Medicine, University of Pennsylvania. Her laboratory has a long-standing interest in elucidating the origins and evolution of human and simian immunodeficiency viruses (HIV/SIV) and studying HIV/SIV gene function and disease mechanisms from an evolutionary perspective. She was the first to describe the extensive in vivo genetic variability of HIV-1 and to discover that recombination between highly divergent viruses is a major driving force of HIV/SIV diversification. Her work includes developing methods for non-invasive detection of SIV in wild-living apes, leading to the identification of chimpanzee and gorilla reservoirs of pandemic and non-pandemic HIV-1. She has demonstrated that SIVcpz, like HIV-1, is pathogenic in its natural chimpanzee host, revealing a significant impact on chimpanzee health and mortality. Her research also uncovered that the chimpanzee CD4 molecule is highly polymorphic, which provides protection against SIV infections, and that primate CD4 receptor diversity is an ancient protection mechanism resulting from a co-evolutionary arms race with primate lentiviruses. Additionally, her studies have challenged previous hypotheses about the co-evolution of malaria parasites and their hosts, showing that P. falciparum and P. vivax originated from parasites infecting African apes. Her work on HIV-1 transmission, virus/antibody coevolution, and the development of a SHIV infection model has advanced understanding of HIV biology and vaccine development. Her current projects focus on exploiting Env trimer conservation for AIDS vaccine design, improving HIV-1 Env immunogens, studying ape Plasmodium infections, natural history of SIVcpz in wild chimpanzees, mechanisms governing HIV-1 rebound, and characterizing SARS-CoV-2 neutralizing antibody responses. She has contributed significantly to the fields of virology, immunology, and global health through her research on viral origins, evolution, and immune responses.

Research topics

• Biology
• Virology
• Immunology
• Sociology
• Computer Science
• Medicine
• Pathology
• Cell biology
• Political Science
• Genetics
• Geography
• Intensive care medicine
• Environmental resource management
• Anatomy
• Environmental planning
• Development economics
• Internal medicine
• Agroforestry
• Forestry
• Ecology
• Evolutionary biology
• Demography
• Biochemistry
• Neuroscience

Selected publications

• Deep mining of the human antibody repertoire identifies frequent and genetically diverse CDRH3 topologies targetable by vaccination

  Proceedings of the National Academy of Sciences · 2026-04-29

  articleOpen access

  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 immunogens capable of engaging them. We determined the frequency and diversity of axe-like CDRH3s 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-electron microscopy 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-HIV. These results illustrate a structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies.

  PublisherOA PDFDOI

• Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates

  Nature Immunology · 2026-02-03 · 5 citations

  articleOpen access

  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 Asn332-glycan-independent antibodies to the conserved V3-glycan epitope of Env with low inhibitory activity indicative of a neutralization activity after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human Asn332-glycan-dependent (type-I) V3-glycan bNAbs but also of a first-of-its-class Asn332-glycan-independent (type-II) V3-glycan bNAb. A single immunization elicits low inhibitory serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. Electron microscopy polyclonal epitope mapping analysis of serum antibodies, antibody cloning and cryogenic electron microscopy analysis reveals that WIN332 elicits Asn332-glycan-independent antibodies with striking 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. WIN332 is an HIV-1 Env protein designed to elicit a new class of Asn332-glycan-independent antibodies (type II) to the V3-glycan site of Env. WIN332 immunization rapidly induces type-II V3-glycan antibodies with low inhibitory activity indicative of a neutralization activity in macaques.

  PublisherDOI

• Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV V2 apex broadly neutralizing antibody development.

  PubMed · 2026-02-13 · 3 citations

  articleOpen access

  Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by 1 of 16 different simian-human immunodeficiency viruses (SHIVs). We identified the V2 apex region of the envelope (Env) as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is a primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as vaccine platforms.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-06

  articleOpen access

  Summary 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.

  PublisherDOI

• Rapidly acquired HIV-1 neutralization breadth in a rhesus V2 apex knockin mouse model after a single bolus immunization.

  PubMed · 2026-02-13 · 2 citations

  articleOpen access

  Current immunization strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multiboost regimens. In rhesus macaques, simian-human immunodeficiency virus (SHIV) infection rapidly drives the development of some bnAb classes sharing structural similarities with those in humans. Here, we generated a knockin (KI) mouse model with B cells bearing the unmutated common ancestor of a V2 apex-targeted bnAb lineage, V033-a. A single immunization with a germline-targeting native-like trimer, Q23-APEX-GT1, recapitulated the ontogeny of the mature rhesus bnAb in KI mice, including rare, disfavored somatic mutations. Resulting antibodies exhibited potent neutralization against a broad panel of heterologous HIV-1 strains. Boosting with Env escape mutant trimers further improved breadth and potency, and cryo-electron microscopy analysis revealed the structural basis for heterologous neutralization breadth. Nonhuman primate and mouse models combined with structure can serve as a platform for identifying and validating immunogens that streamline HIV vaccination regimens.

  PublisherOA PDFDOI

• <i>Plasmodium falciparum</i> CyRPA Glycan Binding Does Not Explain Adaptation to Humans

  Genome Biology and Evolution · 2025-01-27 · 2 citations

  articleOpen accessSenior author

  The human malaria parasite Plasmodium falciparum evolved from a parasite that infects gorillas, termed Plasmodium praefalciparum. The sialic acids on glycans on the surface of erythrocytes differ between humans and other apes. It has recently been shown that the P. falciparum cysteine-rich protective antigen (PfCyRPA) binds human sialoglycans as an essential step in the erythrocyte invasion pathway, while that of the chimpanzee parasite, Plasmodium reichenowi has affinities matching ape glycans. Two amino acid changes, at sites 154 and 209, were shown to be sufficient to switch glycan binding preferences and inferred to reflect adaptation of P. falciparum to humans. However, we show that sites 154 and 209 are identical in P. falciparum and P. praefalciparum, with no other differences located in or near the CyRPA glycan binding sites. Thus, the gorilla precursor appears to have already been preadapted to bind human sialoglycans.

  PublisherDOI

• Structural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies

  The Journal of Experimental Medicine · 2025-07-10 · 10 citations

  articleOpen access

  Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope are desired as vaccine design templates, but few have been described. Here, we report 11 lineages of V2 apex-neutralizing antibodies from simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and determine cryo-EM structures for 9. A single V2 apex-neutralizing lineage accounted for cross-clade breadth in most macaques, and somatic hypermutation relative to breadth was generally low, exemplified by antibody V033-a.01 with <5% nucleotide mutation and 37% breadth (208-strain panel). Envelope complex structures revealed eight different antibody classes (one multi-donor) and the complete repertoire of all five possible recognition topologies, recapitulating canonical human modes of apex insertion and C-strand hydrogen bonding. Despite this diversity in recognition, all rhesus-V2 apex antibodies were derived from reading frame two of the DH3-15*01 gene. Collectively, these results define-in rhesus-the structural and genetic basis of HIV-1 V2 apex recognition and demonstrate unprecedented structural plasticity of a highly selected immunogenetic element.

  PublisherOA PDFDOI

• The HIV-1 envelope cytoplasmic tail protects infected cells from ADCC by downregulating CD4

  mBio · 2025-09-08 · 3 citations

  articleOpen access

  HIV-1-mediated CD4 downregulation is a well-known mechanism that protects infected cells from antibody-dependent cellular cytotoxicity (ADCC). While CD4 downregulation by HIV-1 Nef and Vpu proteins has been extensively studied, the contribution of the HIV-1 envelope glycoprotein (Env) in this mechanism is less understood. While Env is known to retain CD4 in the endoplasmic reticulum (ER) through its CD4-binding site (CD4bs), little is known about the mechanisms underlying this process. Here, we show that the cytoplasmic tail of Env is a major determinant in CD4 downregulation. This function is highly conserved as it was observed with nine different infectious molecular clones from four clades. The small but significant accumulation of CD4 at the surface of cells infected with Env cytoplasmic tail-deleted viruses is sufficient to trigger Env to adopt a more "open" conformation. This prompted recognition of HIV-1-infected cells by plasma from people living with HIV (PLWH) and several families of CD4-induced (CD4i) antibodies, leading to the elimination of these cells by ADCC. While cytoplasmic tail truncations are known to enhance Env expression at the cell surface, this did not fully explain the increased recognition of infected cells by CD4i antibodies and plasma from PLWH. Introduction of the CD4bs D368R mutation, which abrogates CD4 interaction, decreased Env recognition and ADCC. Overall, our results show that CD4 downregulation by the cytoplasmic tail of Env contributes to the protection of infected cells from ADCC.IMPORTANCEHIV-1-mediated CD4 downregulation is a central mechanism involved in the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC). CD4 downregulation prevents the premature interaction between HIV-1 envelope glycoproteins (Env) and CD4, which would otherwise "open" Env and expose vulnerable epitopes recognized by CD4-induced antibodies present in the plasma from people living with HIV. While the mechanisms of CD4 downregulation by the viral accessory proteins Nef and Vpu have been elucidated, the function of Env in this process is less clear. Here, we show that the cytoplasmic tail of Env plays an important role, thus contributing to the protection of infected cells from ADCC.

  PublisherDOI

• Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-06 · 8 citations

  preprintOpen access

  Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by one of 16 different simian-human immunodeficiency viruses (SHIVs). We identified V2 apex as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is the primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as novel vaccine platforms. One sentence summary: B cell priming is the primary bottleneck to HIV-1 V2 apex bNAb elicitation.

  PublisherOA PDFDOI

• Betriebsfeste Auslegung von Wälzlagerkäfigen durch Dynamiksimulation mit integrierter Festigkeitsanalyse Reliable Design of Rolling Bearing Cages Through Dynamic Simulation with Integrated Strength As...

  VDI Verlag eBooks · 2025-01-01

  book-chapter1st authorCorresponding
  PublisherDOI

Recent grants

• NIH Grant R37AI050529

  NIH · $5.7M · 2019

• NIH Grant R01AI025291

  NIH · $2.0M · 1998

• NIH Grant P60AR036834

  NIH · $18.6M · 2003

• NIH Grant R01AI091595

  NIH · $5.3M · 2021

• NIH Grant R01AR033962

  NIH · $2.4M · 1999

Frequent coauthors

• George M. Shaw

  California University of Pennsylvania

  538 shared

• Paul M. Sharp

  University of Edinburgh

  313 shared

• Frédéric Bibollet‐Ruche

  University of Pennsylvania

  300 shared

• Martine Peeters

  296 shared

• Brandon F. Keele

  Frederick National Laboratory for Cancer Research

  263 shared

• Elizabeth Bailes

  University of Nottingham

  211 shared

• Yingying Li

  University of Pennsylvania

  210 shared

• Bette Korber

  New Mexico Consortium

  182 shared

Labs

• Hahn LabPI