About

George M. Shaw, M.D., Ph.D., is a Professor of Medicine (Hematology-Oncology) at the University of Pennsylvania and a member of the Abramson Cancer Center and the PENN Center for AIDS Research. His laboratory has a longstanding interest in the molecular biology and immunopathogenesis of human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV). His research has included the first molecular clones of HIV-1, the discovery of the quasispecies nature of HIV-1 in vivo, and the investigation of viral replication dynamics and persistence in vivo. Shaw's work extends to the molecular identification and biological characterization of transmitted/founder HIV-1 genomes, as well as studies on simian immunodeficiency virus (SIV) infection in rhesus macaques and HCV infection in humans. His recent efforts focus on developing novel strategies for constructing SHIV chimeras that replicate efficiently in rhesus macaques and induce broadly neutralizing antibodies, serving as models for HIV-1 vaccine development. His projects aim to elucidate HIV-1 transmission, persistence, and pathogenesis, as well as the development of vaccine strategies and understanding viral-host interactions that underpin immune responses and virus evolution.

Research topics

• Biology
• Immunology
• Virology
• Cell biology
• Computational biology
• Molecular biology
• Computer Science
• Anatomy
• Genetics
• Evolutionary biology
• Neuroscience
• Chemistry

Selected publications

• Mechanisms of early-life immunity associated with induction of heterologous HIV-1 neutralizing antibodies 9283

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description A goal of an HIV-1 vaccine is induction of broadly neutralizing antibodies (bnAbs) that prevent infection of different strains. Previous studies have shown that infants and children living with HIV-1 generate bnAbs more frequently than adults. Studying neonate and adult rhesus macaques (RM) infected with simian-HIV (SHIV), we interrogated the permissive immunological environment for bnAb induction in pediatric populations. We studied 11 pairs of SHIV-infected RMs (N = 22), collecting blood and tissue samples up to 24 months post-infection. Viral load was quantified via qPCR of SIV gag RNA copies/mL of plasma. Blood-derived monoclonal (m) Abs and plasma samples were tested for HIV/SHIV neutralization by TZM-bl assay. Lymph node-derived germinal center (GC) B and T cell phenotyping was via flow cytometry. Neonates and adults had similar viral peaks, but neonates maintained 1-2 logs higher mean viremia over time. By 24 months, 7/11 (64%) neonates developed plasma heterologous HIV-1 nAbs, in contrast to 2/11 (18%) adults. From a young RM, we isolated (BEAM-Ab assay 10X Genomics) three mAbs that neutralized up to ∼90% of viral particles in heterologous tier 2 HIV-1 strains, of which two neutralized ∼13% of 119 strains (GM IC50=∼8-11µg/ml). Also, neonates had fewer GC CD4+ T regulatory cells than adults. We defined mechanisms of SHIV immunity that may inform future pediatric vaccine strategies in humans to elicit heterologous HIV-1 nAbs that can mature to bnAbs prior to sexual debut. Topic Categories Viral Immunology (VIR)

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-09

  preprintOpen 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 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.

  PublisherOA PDFDOI

• Persistence of CMV-specific anti-HIV CAR T cells after adoptive immunotherapy

  Journal of Virology · 2025-04-10 · 1 citations

  articleOpen access

  ABSTRACT The success of chimeric antigen receptor (CAR)-T cell (Tc) immunotherapy in refractory B-cell acute lymphoblastic leukemia (B-ALL) suggests adaptation of this strategy toward HIV. Because cytomegalovirus (CMV) vaccine vectors generated Tc responses that controlled viral replication, these studies aim to genetically modify CMV-specific Tc with HIV-CAR2 vectors and link HIV immunotherapy to persistent CMV antigen stimulation. To mimic a clinical scenario, rhesus macaques were challenged with the CCR5-tropic simian/human immunodeficiency virus (SHIV-D) prior to antiretroviral therapy (ART). Autologous CMV-specific Tc were transduced with the control CEA-CAR2 or CD4-CAR2/maC46 vectors and reinfused. After stopping ART, the plasma viral load (PVL) in the control rebounded and was sustained above 1.7 × 10 4 copies/mL; PVL in CD4-CAR2-treated animals was delayed up to 6 weeks and 10-fold lower. The CD4 CAR-Tc frequency peaked at day 7 and was detected in lymphoid tissues at 6 weeks. Both CEA-CAR2 and CD4-CAR2 persisted in PBMCs for about 2 years, which indicates that the CMV-specific CAR Tc were maintained based on their CMV specificity. However, long-term PVL was stable in all animals. Thus, CMV-specific CAR-Tc were active initially, persisted long term, but failed to control viral replication. IMPORTANCE Because of latent viral reservoirs and a dysfunctional immune response, HIV replication rebounds when antiretroviral therapy is interrupted. Therefore, cytomegalovirus (CMV)-specific Tc were genetically modified with anti-HIV CD4-CAR2 vectors to link the targeting of the HIV envelope to the persistent CMV immune response. In this clinical scenario with simian/human immunodeficiency virus (SHIV) challenge and antiretroviral therapy (ART) suppression, early activity of the CAR Tc delayed rebound in the rhesus macaque/SHIV challenge model. However, even with long-term persistence of CAR Tc in the blood, control of viral replication was not achieved. These data suggest that CAR Tc will require additional interventions to cure HIV infection.

  PublisherDOI

• Consistent Induction of Broadly Neutralizing HIV Antibodies by a Novel Two-Step Mechanism Informs Immunogen Design

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-06 · 3 citations

  preprintOpen accessSenior authorCorresponding

  A major obstacle confronting HIV-1 vaccine and cure research is the lack of an outbred animal model for rapid and consistent induction of broadly neutralizing antibodies (bNAbs). We designed an epitope-focused simian-human immunodeficiency virus (SHIV.5MUT) that elicited broad and potent V3-glycan-targeted antibodies within a year of infection in 14 of 22 macaques compared with 0 of 14 control animals. SHIV.5MUT elicited bNAbs by a novel two-step mechanism, inducing an initial wave of V1-directed antibodies that selected for Envs with shortened, hypoglycosylated V1 loops, which in turn primed V3-glycan bNAb precursors. Rhesus bNAbs were immunogenetically and structurally diverse, closely resembling human V3-glycan bNAbs. Env-bNAb coevolution revealed a diverse repertoire of bNAb precursors and the Env variants that matured them, yielding a molecular blueprint for vaccine design.

  PublisherOA PDFDOI

• Status of HIV vaccine development: progress and promise

  Journal of the International AIDS Society · 2025-05-01 · 3 citations

  articleOpen accessSenior author

  HIV Vaccine Awareness Day (HVAD) each year commemorates President Bill Clinton's 1997 declaration that “only a truly effective preventive HIV vaccine can limit and eventually eliminate the threat of AIDS.” Here, we review recent progress that the HIV vaccine field has made in inducing protective broadly neutralizing antibodies (bnAbs) that can prevent HIV acquisition. Several papers provide further review and discussion of the concepts discussed in this Viewpoint [1-3]. An HIV bnAb-based vaccine has been difficult to develop because of the extensive genetic variability of HIV, its heavily glycosylated and conformationally masked envelope (Env) surface protein and the need to induce durable high levels of multiple bnAb specificities to achieve protection [4]. In addition, because HIV mutates so rapidly, it will be necessary to induce multiple types of bnAbs to fully cover the broad range of variants. One solution to inducing naturally disfavoured bnAbs is to design immunogens that target naïve bnAb B cell precursors, expand them and select for improbable mutations that are roadblocks for bnAb affinity maturation [5, 6]. Following naïve B cell priming, sequential immunization with Env immunogens with increasing affinities will be needed to mature bnAb lineages along desired pathways [5, 7]. Thus, iterative vaccine design in animal models and in small Phase I clinical trials is required to assess the many steps in such a complex vaccine strategy. Such trials in the HIV Vaccine Trials Network (HVTN) are called Discovery Medicine trials [8]. Figure 1 shows the bnAb target epitopes on the HIV envelope for which a degree of success in inducing B cell lineages has been achieved by vaccination in immunoglobulin humanized mice, non-human primates or humans. What follows here are brief updates on trials that have initiated immunization with bnAb B cell lineages primarily in either non-human primates or in humans by vaccination. Gp41 membrane proximal external region (MPER) bnAbs are among the most broadly reactive HIV antibodies. An MPER peptide-liposome priming immunogen designed to mimic gp41 bnAb binding sites and bind to a prototype bnAb naïve B cell receptor was used in the HVTN 133 clinical trial. B cells were induced that bound to the proximal MPER bnAb epitope—the most potent of these antibodies neutralized 35% of heterologous clade B and 17% of global HIV isolates [9]. The HVTN 133 trial demonstrated that antibody mutations that take years to develop in people living with HIV (PLWH) can be induced by vaccination in months. Work is ongoing to expand the breadth and potency of induced bnabs by the design of boosting immunogens to target MPER sequences of contemporary global HIV strains. CD4 binding site (CD4bs) bnAbs are both potent and broad and thus represent key vaccine targets. There are two types of CD4bs bnAbs, which include those that mimic CD4 binding through a gene-restricted CDRH2 motif and others that utilize CDRH3 to bind the CD4bs [4]. CD4bs immunogens are based on HIV envelope (Env) proteins identified during natural infection or engineered to bind to either type of CD4bs bnAb precursor B cell lineages. These immunogens successfully activate and expand CD4 mimicking CD4bs naïve B cell precursors and intermediate antibodies in humanized mouse strains [10], non-human primates [11, 12] and humans [13]. CDRH3-mediated neutralizing antibody lineages have also been induced in the HVTN 300 trial using a stabilized germline-targeting Env trimer [14]. CD4bs immunogens are being tested in a number of clinical trials including IAVI 002, HVTN 301, HVTN 320, HVTN 321, ACTG 5422 and IAVI C101. V3-glycan bnAbs require long CDRH3 segments or nucleotide insertion mutations and thus are disfavoured by the immune system. However, using germline-targeting immunogens that bind to particular V3-glycan bnAb naïve B cell precursors, V3-glycan bnAb precursors have been induced in non-human primates (NHPs) [15] and in humanized mice [16]. V3-glycan bnAb targeting Envs are being tested in HVTN 144, HVTN 307 and HVTN 321 clinical trials. V2 apex bnAbs also have long CDRH3s, and like V3-glycan bnAbs, their precursors are relatively rare in the naïve B cell repertoire. Nonetheless, V2 apex immunogens have been designed that bind to certain V2 B cell precursor cells and have activated and expanded V2 apex bnAb lineages in humanized mice [17]. Immunogens that target the V2 apex are scheduled to be tested in HVTN trial HVTN 322. The HIV fusion domain is expressed on the prefusion HIV Env and is a target for bnAb induction. HIV-1 fusion domain vaccines include HIV-1 fusion peptides arrayed on carrier molecules immunogens and will be tested in the NIH VRC trial, VRC020. BnAbs to the fusion domain have been induced in mice [18] and in monkeys [19], and fusion domain-targeted bnAbs protect monkeys from Simian-Human Immunodeficiency Virus (SHIV) infection [20], and immunogens have been tested in HVTN 303 and are schedule for testing in VRC020. These recent successes have provided the proof-of-concept that bnAb lineages can be induced in animals and humans. It is clear that naïve B cell/germline targeting immunogens, followed by boosting with sequential immunogens, will be required to produce a bnAb-based HIV vaccine. Other principles are that it will be necessary to induce multiple types of bnAbs to avoid HIV escape, that boosting immunogens will need to keep bnAb lineages on track and not induce competing off-track antibodies, and that immunogens will need to induce durable bnAb responses. In addition, a successful immunogen may need to induce CD4+ T cell help and likely induce protective CD8+ T cells to eliminate any virions or virus-infected cells that escape bnAb neutralizing activity [1]. To date, no immunization regimen has induced the types of neutralization responses required to achieve the degree of breadth and potency needed for consistent protection by a vaccine. Artificial intelligence algorithms trained to rapidly select Env mutants that will boost bnAb lineages to heterologous breath and potency may accelerate immunogen design. Thus, the road to a successful HIV vaccine is essentially to learn how to engineer the immune system to stimulate and mature rare neutralizing antibodies that infrequently occur in PLWH. Once accomplished, a multivalent immunogen will need to be formulated for a practical vaccine. While a difficult task, the rewards will be enormous by protecting those at risk from HIV acquisition and ending the HIV epidemic. Work is ongoing to design vaccine Env immunogens with many bnAb triggering sites on the same immunogen to minimize the number of vaccine components. Moreover, once the full set of rules are deciphered regarding the induction of disfavoured B cell responses, the same strategies can be applied to make other difficult-to-make vaccines. Thus, we can expect technologies developed in the HIV field to continue to enrich other fields as the HIV vaccine work progresses to success. BFH, GS, BHH, KW and KOS have patents on vaccine constructs discussed in this paper. BFH wrote the first draft of the paper. BBH, GMS, KW, KOS and LRB edited the paper. KW produced Figure 1. The authors acknowledge Whitney Beck for editorial assistance. All authors were supported by HHS, NIH and NIAID UM1 grant AI144371 for the Consortia for HIV/AIDS Vaccine Development. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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• 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

• 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 accessSenior authorCorresponding

  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

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

  Cell Reports · 2025-06-01 · 5 citations

  articleOpen accessSenior author

  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 cryoelectron microscopy (cryo-EM) structure of RHA10 with the 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 that glycan deletions in infecting SHIVs could induce CD4bs bNAbs. To test this hypothesis, we constructed SHIV.CH505 variants with CD4bs-proximal glycan deletions. Infection of 11 macaques resulted in accelerated CD4bs bNAb responses in 9 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 serve as a model for HIV vaccine design.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-12 · 8 citations

  preprintOpen accessCorresponding

  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. Highlights: Isolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaquesCryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognitionAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame twoThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodiesStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition modePropose 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 naïve rhesus repertoireDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity.

  PublisherOA PDFDOI

• Viral Envelope Evolution in Simian–HIV-Infected Neonate and Adult-Dam Pairs of Rhesus Macaques

  Viruses · 2024-06-25 · 1 citations

  articleOpen access

  We recently demonstrated that Simian-HIV (SHIV)-infected neonate rhesus macaques (RMs) generated heterologous HIV-1 neutralizing antibodies (NAbs) with broadly-NAb (bNAb) characteristics at a higher frequency compared with their corresponding dam. Here, we characterized genetic diversity in Env sequences from four neonate or adult/dam RM pairs: in two pairs, neonate and dam RMs made heterologous HIV-1 NAbs; in one pair, neither the neonate nor the dam made heterologous HIV-1 NAbs; and in another pair, only the neonate made heterologous HIV-1 NAbs. Phylogenetic and sequence diversity analyses of longitudinal Envs revealed that a higher genetic diversity, within the host and away from the infecting SHIV strain, was correlated with heterologous HIV-1 NAb development. We identified 22 Env variable sites, of which 9 were associated with heterologous HIV-1 NAb development; 3/9 sites had mutations previously linked to HIV-1 Env bNAb development. These data suggested that viral diversity drives heterologous HIV-1 NAb development, and the faster accumulation of viral diversity in neonate RMs may be a potential mechanism underlying bNAb induction in pediatric populations. Moreover, these data may inform candidate Env immunogens to guide precursor B cells to bNAb status via vaccination by the Env-based selection of bNAb lineage members with the appropriate mutations associated with neutralization breadth.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI035467

  NIH · $1.4M · 1997

• NIH Grant R01AI033826

  NIH · $1.1M · 1998

• Targeting 5' leader-encoded defective ribosomal products for HIV T cell vaccines

  NIH · $3.6M · 2016–2022

• NIH Grant R21AI106000

  NIH · $452k · 2016

• Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design

  NIH · $3.2M · 2021–2026

Frequent coauthors

• Beatrice H. Hahn

  University of Pennsylvania

  538 shared

• Frédéric Bibollet‐Ruche

  University of Pennsylvania

  268 shared

• Brandon F. Keele

  Frederick National Laboratory for Cancer Research

  264 shared

• Paul M. Sharp

  University of Edinburgh

  249 shared

• Martine Peeters

  214 shared

• Yingying Li

  University of Pennsylvania

  192 shared

• Elizabeth Bailes

  University of Nottingham

  191 shared

• Mario L. Santiago

  University of Colorado Anschutz Medical Campus

  168 shared

Labs

• Shaw LabPI