About

Bruce Walker is a Professor of the Practice and a Core Member at the Ragon Institute of MGH, MIT, and Harvard. His research investigates cellular immune responses in chronic human viral infections, with a particular focus on HIV immunology and vaccine development. His laboratory aims to define the interplay of immunologic, virologic, and host genetic factors that determine control of human viral infections, specifically addressing HIV infection. His work guides vaccine development and immunotherapeutic interventions, contributing significantly to understanding HIV-specific T cell functions, immune responses, and viral control mechanisms. Walker has received numerous awards, including the NIH Merit Award, the Bernard Fields Lectureship, and memberships in the American Academy of Arts and Sciences and the National Academy of Medicine.

Research topics

• Biology
• Virology
• Internal medicine
• Medicine
• Genetics
• Immunology
• Cell biology
• Cancer research
• Molecular biology
• Obstetrics
• Computational biology

Selected publications

• Bayesian estimation of HIV acquisition dates for prevention trials

  mBio · 2025-09-09 · 3 citations

  articleOpen access

  Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, "true DDA" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.

  PublisherDOI

• SLAMF6 enables efficient attachment, synapse formation, and killing of HIV-1-infected CD4 ⁺ T cells by virus-specific CD8 ⁺ T cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-22 · 1 citations

  preprintOpen access

  ABSTRACT Efficient recognition and elimination of HIV-1-infected CD4 + T cells by cytotoxic CD8 + T cells (CTLs) require target cell engagement and the formation of a well-organized immunological synapse. Surface proteins belonging to the SLAM family are known to be crucial for stabilizing the immunological synapse and regulating antiviral responses during lymphotropic viral infections. In the context of HIV-1, there have been reports of SLAMF6 down-regulation in HIV-1-infected CD4 + T cells; however, the significance of this modulation for CTL function remains unclear. In this investigation, we used CTL lines from People living with HIV (PLWH) to examine the impact of SLAMF6 blockade on three pivotal processes: (1) the formation of CD8 + -CD4 + T-cell conjugates, (2) the establishment of the immunological synapse, and (3) the killing and cytokine production capacity of HIV-1-specific CTLs during HIV-1 infection. Our findings reveal that the inability to form CD8 + -CD4 + T-cell conjugates following incubation with an anti-SLAMF6 blocking antibody is primarily attributable to a defect in actin ring formation at the immunological synapse. Furthermore, SLAMF6 blockade leads to a reduction in the killing efficiency of HIV-1-infected CD4 + T cells by HIV-1-specific CTLs, underscoring the critical role of SLAMF6 in cytolytic function. This study highlights the importance of SLAMF6 receptors in modulating cytotoxic antiviral responses, shedding light on potential avenues for manipulation and enhancement of this pathway in the context of HIV and other lymphotropic viral infections.

  PublisherOA PDFDOI

• CD8+ T cell stemness precedes post-intervention control of HIV viraemia

  Nature · 2025-12-01 · 18 citations

  articleOpen access

  Abstract Interventions to induce lasting human immunodeficiency virus (HIV) remission are needed to obviate the requirement for lifelong antiretroviral therapy. Durable post-intervention control (PIC) of viraemia has been achieved in a subset of people following administration of broadly neutralizing anti-HIV-1 antibodies (bNAb) and analytical interruption of treatment 1–4 . Previous studies support a role for CD8 + T cells in PIC 5–9 , but the precise features of CD8 + T cells involved remain unclear. Here we mapped and functionally profiled CD8 + T cell responses to autologous HIV epitopes using longitudinal samples from four analytical treatment interruption trials in bNAb recipients. PIC was associated with superior pre-intervention HIV-specific CD8 + T cell proliferative capacity, stem-cell-like memory phenotype and recall cytotoxicity against autologous HIV peptide-pulsed CD4 + T cells. CD8 + T cell stemness was increased further following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multi-modal single-cell analyses revealed molecular features associated with PIC and HIV-specific CD8 + T cell stemness, including signatures of metabolic fitness and reduced T cell exhaustion. These results identify immune features that precede subsequent PIC to inform the development of combination immunotherapies that will elicit durable HIV remission.

  PublisherDOI

• Author response: Differences in HIV-1 reservoir size, landscape characteristics, and decay dynamics in acute and chronic treated HIV-1 Clade C infection

  2025-02-20 · 1 citations

  peer-reviewOpen access

  Extremely early antiretroviral therapy during HIV-1 subtype C infection leads to faster decline in genome-intact viruses, reduced genetic complexity, and immune escape, and may enhance reservoir clearance with additional interventional strategies.

  PublisherDOI

• Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies

  PLoS Pathogens · 2025-06-23 · 1 citations

  articleOpen access

  Broadly neutralizing antibodies (bnAbs), passively administered or elicited through vaccination, are a promising strategy for novel HIV prevention, treatment or inducing ART-free remission. However, HIV diversity and evolution are a barrier to the efficacy of bnAbs and there is therefore an urgent need for continuous virus surveillance to identify bnAbs with optimal neutralization breadth and potency against transmitted/founder (TF) viruses, especially in high-burden regions. We determined the neutralization sensitivity of TF viruses isolated within seven days after first detection of heterosexually acquired infection from young women 18-23 years old (n = 39) and within 1 month after birth from in-utero infected infants (n = 21) from FRESH and Baby Cure cohorts respectively, in KwaZulu-Natal, South Africa, where HIV-1 subtype C predominates. Neutralization sensitivities of 47 viruses from FRESH and 21 viruses from Baby Cure were assessed against nine bnAbs targeting different regions on the HIV-1 Env trimer. HIV-1 env sequences within and between bnAb epitopes were compared with database. The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Furthermore, VRC07-523LS showed higher neutralization breadth and potency than other bnAbs against Baby Cure TF viruses (p = 0.02). Interestingly, CAP256-VRC26.25 and PGT151 had lower neutralization coverage against infant TF viruses (<60% coverage). Moreover, 40% of infants TF had escape mutations within the V2 loop compared to 28% observed in FRESH and these mutations may explain the observed differences in neutralization sensitivities. However, few mutations were observed in gp120-gp41 interface in both adults and infants. Our findings suggest that intervention studies may have to consider different antibody combinations in adult versus paediatric settings. Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings.

  PublisherDOI

• Differences in HIV-1 reservoir size, landscape characteristics, and decay dynamics in acute and chronic treated HIV-1 Clade C infection

  eLife · 2025-02-20 · 10 citations

  articleOpen access

  Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are a barrier to cure efforts. Early antiretroviral therapy (ART) enables post-treatment viral control in some cases, but mechanisms remain unclear. We hypothesised that ART initiated before peak viremia impacts HIV-1 subtype C reservoirs. We studied 35 women at high risk of infection from Durban, South Africa, identified with hyperacute HIV by twice-weekly HIV-RNA testing. Participants included 11 starting ART at a median of 456 (297–1203) days post-onset of viremia (DPOV) and 24 at 1 (1–3) DPOV. Peripheral blood mononuclear cells (PBMCs) were used to measured total HIV-1 DNA by droplet digital PCR (ddPCR) and sequence viral reservoir genomes by full-length proviral sequencing (FLIP-seq). ART during hyperacute infection blunted peak viremia (p&lt;0.0001), but contemporaneous total HIV-1 DNA did not differ (p=0.104). Over 1 year, a decline of total HIV-1 DNA was observed in early treated persons (p=0.0004), but not late treated. Among 697 viral genome sequences, the proviral genetic landscape differed between untreated, late treated, and early treated groups. Intact genomes after 1 year were higher in untreated (31%) versus late treated (14%) and early treated (0%). Treatment in both late and early infection caused more rapid decay of intact (13% and 51% per month) versus defective (2% and 35%) viral genomes. However, intact genomes persisted 1 year post chronic treatment but were undetectable with early ART. Early ART also reduced phylogenetic diversity of intact genomes and limited cytotoxic T lymphocyte immune escape variants in the reservoir. Overall, ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding but was associated with rapid intact viral genome decay, reduced genetic complexity, and limited immune escape, which may accelerate reservoir clearance in combination with other interventional strategies.

  PublisherDOI

• Distinct viral reservoirs and immune signatures in individuals on long-term antiretroviral therapy with perinatally acquired HIV-1

  Cell Reports Medicine · 2025-05-29 · 14 citations

  articleOpen access

  T cell response. Collectively, our data suggest that long-term ART initiated in early life following perinatal transmission may facilitate an immune environment better equipped to restrict the HIV-1 reservoir.

  PublisherDOI

• CD8 ⁺ T cell recall cytotoxicity during antiretroviral therapy is associated with limited HIV-1 reservoir size and activity

  medRxiv · 2025-10-13

  preprintOpen access

  ABSTRACT HIV-1 persists during antiretroviral therapy (ART), resulting in rebound viremia after treatment interruption. HIV-specific CD8 + T cell functionality is typically not restored by ART but may improve following prolonged treatment and was recently associated with post-intervention viral control. To evaluate the prevalence and impact of T cell immune function on HIV-1 persistence during prolonged ART, we mapped and functionally characterized CD8 + T cell responses that target virus reservoirs in sixty people with HIV-1 (PWH) who initiated therapy during chronic infection. Unexpectedly, 17% of participants exhibited robust proliferation and recall cytotoxicity against one or more autologous proviral epitopes at levels commensurate with spontaneous HIV-1 controllers, a group representing less than 1% of PWH. These functional responses were associated with smaller and less transcriptionally active HIV-1 reservoirs during ART. During an analytical treatment interruption, in vivo cytotoxic recall of phenotypically divergent HIV epitope-specific CD8 + T cell clonotypes trailed viral rebound but coincided with its attenuation prior to ART resumption. Our study reveals the unexpected prevalence of highly functional CD8 + T cells targeting autologous HIV-1 reservoirs among treated PWH and their potential impacts on viral persistence and rebound. These findings underscore a need for multimodal immunotherapeutic strategies capable of eliciting, restoring, or accelerating recall cytotoxicity toward achieving durable and scalable HIV-1 remission.

  PublisherOA PDFDOI

• Guidelines for T cell nomenclature

  Nature reviews. Immunology · 2025-11-18 · 26 citations

  articleOpen access
  PublisherOA PDFDOI

• Polymorphic residues in HLA-B that mediate HIV control distinctly modulate peptide interactions with both TCR and KIR molecules

  Structure · 2024-05-10 · 5 citations

  articleOpen access

  <h2>Summary</h2> Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective <i>HLA-B^∗5701</i> allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8⁺ T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B^∗5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control.

  PublisherDOI

Recent grants

• T-cell-mediated targeting of therapeutics to HIV reservoirs

  NIH · $2.1M · 2014–2019

• NIH Grant P01AI080192

  NIH · $25.2M · 2015

• NIH Grant R01AI040873

  NIH · $2.6M · 2007

• Understanding and Reversing T Cell Dysfunction to Control and Eliminate Persistent HIV Reservoirs

  NIH · $2.1M · 2019–2024

• Molecular networks of HIV-specific CD4 T cell help to B cells

  NIH · $1.7M · 2015–2021

Frequent coauthors

• Philip Goulder

  Ragon Institute of MGH, MIT and Harvard

  1047 shared

• Thumbi Ndung’u

  University of KwaZulu-Natal

  790 shared

• Todd M. Allen

  Massachusetts General Hospital

  681 shared

• Christian Brander

  564 shared

• Marcus Altfeld

  German Center for Infection Research

  535 shared

• Xu G. Yu

  Ragon Institute of MGH, MIT and Harvard

  492 shared

• Eric Rosenberg

  Massachusetts General Hospital

  491 shared

• Paul Klenerman

  John Radcliffe Hospital

  432 shared

Labs

• Bruce Walker LabPI

Awards & honors

• Bernard Fields Lectureship (2015)
• NIH Merit Award (2011)
• NIH Merit Award (2004)
• American Academy of Arts and Sciences (2010)
• National Academy of Medicine (2009)