10-1074 / National Institute of Allergy and Infectious Diseases, Rockefeller University, Gilead - LARVOL DELTA

Haplotype and diversity signatures of ultra-soft selective sweeps in HIV-1. (PubMed, bioRxiv) - "These "ultra-soft" sweep signatures more closely resemble genetic patterns in a treatment non-responder without an adaptive response to 10-1074 than those of two other trial participants where adaptation occurred via harder selective sweeps. Our results demonstrate that HIV can adapt to a broadly neutralizing antibody treatment while retaining nearly all of its standing genetic diversity and that selection scans dependent on regional diversity and haplotype homozygosity signatures fail in this "ultra-soft" regime."

Journal • Human Immunodeficiency Virus • Infectious Disease

Immunological comparison of viral control in the RIO trial versus HIV elite and post-treatment controllers (AIDS 2026) - "The RIO trial tested two LS-bNAbs, 10-1074 and 3BNC117, during analytical treatment interruption (ATI) and found that 25% of participants remained off ART after two years. VECs exhibited stronger baseline CD8+ responses than BCs and demonstrated viral inhibition capacity comparable to ECs. These findings suggest that bNAbs can help harness pre-existing HIV-specific immunity to support viral control."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • HAVCR2 • LAG3 • TIGIT

Modeling quantifies in vivo neutralization, Fc-mediated killing, and resistance in human clinical trials of five anti-HIV broadly neutralizing antibodies. (PubMed, bioRxiv) - "We therefore performed a mathematical modeling meta-analysis which integrated four clinical trials and reproduced serial bnAb concentrations, viral loads, and bnAb sensitivities (IC50) in 43 viremic trial participants who received an infusion of VRC01, VRC01LS, VRC07-523LS, 3BNC117 or 10-1074. For each bnAb, our best model identified a scaling factor of 36-462 to pro j ect in vivo activity from in vitro IC50, quantified Fc-mediated infected cell killing in humans over time, and pro j ected the timing of bnAb-resistant strain emergence. Using this holistic profile, VRC07-523-LS was generally optimal."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1. (PubMed, bioRxiv) - "We have previously shown that PD-L1-mediated immune shielding improves the consistency of AAV-delivered bNAb 3BNC117 expression from muscle tissue in rhesus macaques. Here, we test the breadth of this approach with another bNAb, 10-1074...Histopathological profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a broad strategy to prolong transgene expression from muscle-directed AAV-delivered biologics."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • PD-L1

In vivo affinity maturation of engineered B-cell receptors (ASGCT 2026) - "Results B cells edited in this way to express the HIV-1 broadly neutralizing antibodies 10-1074 and VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated recipient mice...b, The human anti-SARS- CoV-2 antibody ZCB11 was affinity matured in mice vaccinated with the receptor-binding domain of Omicron variant BA.5. One resulting variant, ZCB11-v9, improved neutralization against most SARS-CoV-2 variants, notably by 61-fold against the BA.5 immunogen strain (dark line)."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Therapeutic efficacy of AAV-delivered HIV-1 bNAbs to prevent SHIV rebound in rhesus macaques (ASGCT 2026) - "Macaques in the treatment group received AAV9 vectors encoding 10-1074 and 3BNC117 co-delivered with AAV9 vectors encoding PD-L1. Our ongoing study reveals that the co-delivery of PD-L1 is sufficient to achieve therapeutic concentrations of bNAb expression in rhesus macaques that can suppress a SHIV infection without ART. Additionally, these results suggest AAV-delivered bNAbs are a possible alternative to ART therapy in SHIV-infected macaques."

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • PD-L1

Tertiary lymphoid structures undermine muscle-targeted AAV delivery of biologics (ASGCT 2026) - "Methods Five groups of rhesus macaques (n=6 per group) received 2.5×10¹² vg kg⁻¹ of each of the following vectors: 1) AAV9.PD-L1; 2) AAV9.10-1074; 3) AAV9.10-1074 and AAV9.PD-L1; 4) AAV9.3BNC117 and 5) AAV9.3BNC117 and AAV9.PD-L1. The formation and persistence of TLSs at the administration site may be a previously unrecognized mechanism by which ADA persists. Thus, PD-L1-mediated immune shielding may be a strategy to prolong transgene expression of AAV-delivered biologics and preserve the health of the muscle."

IO biomarker • Fibrosis • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • PD-L1

Diverse paths to broadly neutralizing antibody escape among HIV-1 strains. (PubMed, Nat Microbiol) - "Here we developed a medium-to-high throughput approach to determine the mutations that confer resistance to neutralization by the bnAbs 3BNC117 and 10-1074 currently in clinical development. Some 3BNC117 resistance mutations conferred resistance to additional bnAbs targeting the same or different epitopes, and unconventional escape mechanisms were occasionally encountered. These data provide a rationale for selecting bnAb combinations that are most likely to achieve treatment success."

Journal • Human Immunodeficiency Virus • Infectious Disease

Recurrent mutations drive rapid HIV escape from two broadly neutralizing antibodies in vivo. (PubMed, Proc Natl Acad Sci U S A) - "We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full-length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Despite this, 3BNC117 escape mutations can still emerge recurrently within their host. Our findings map longitudinal in vivo antibody escape across 20 diverse clade B HIV intrahost populations and reveal clinically relevant resistance dynamics that highlight how combination bNAb therapies will need to contend with extensively recurring escape mutations and dependence on genetic background."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Immune correlates of HIV-1 rebound during broadly neutralizing antibody treatment in young children. (PubMed, J Clin Invest) - "We conducted a detailed analysis of proviral reservoir dynamics and antiviral immune responses in a unique group of young children from Botswana who started ART at birth and then stopped standard ART while receiving the bnAbs 10-1074 and VRC01-LS in a subsequent clinical trial. HIV-specific T cell responses were low in all study participants and unrelated to viral reservoir sizes or clinical outcomes following ART interruption. These results suggest that, in young children, specific NK cell subsets and KIR-HLA interactions might be linked to HIV-1 rebound kinetics after substitution of standard ART with bnAbs."

Clinical • Journal • Human Immunodeficiency Virus • Infectious Disease • HLA-B • KIR2DL1 • KLRC1

HIV-induced sialoglycans on infected CD4+ T cells promote immune evasion from myeloid cell-mediated killing. (PubMed, Nat Commun) - "Treatment with 10-1074-SiaD in female humanized mice infected with HIV reduces viral load and decreases inflammation. These findings reveal an immune evasion mechanism exploited by HIV to evade myeloid cell immune surveillance and highlight the potential of targeting sialoglycan-Siglec interactions to improve immune clearance of HIV-infected cells."

Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD33 • CD4

Correlates of HIV-1 control after combination immunotherapy. (PubMed, Nature) - P1/2 | "We performed a single-arm, proof-of-concept study in ten people with HIV on ART combining the following three approaches: (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (NCT04357821). Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower median viral load following peak viremia off ART. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD8 • IL12A

Triple rAAV9 Vector Combinations Encoding Broadly Neutralizing Antibodies Effectively Suppress HIV-1 Infection in Humanized Mice. (PubMed, Int J Mol Sci) - "We demonstrated that mice preventively treated with CombiMab-1 or CombiMab-2 did not develop viremia and maintained human CD4+ T-lymphocyte counts following viral challenge, in contrast to control animals. These results demonstrate the significant protective capacity of CombiMab-1 and CombiMab-2 against HIV-1 challenge."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4

In Vivo Production of Anti-HIV Antibody from Engineered Primate Hematopoietic Stem and Progenitor Cells (ESGCT 2024) - "To address these issues, we engineered NHP hematopoietic stem and progenitor cells (HSPC) by targeting the immunoglobulin heavy chain locus, IGH, using Cas12a ribonucleoprotein complex to integrate a non-viral transgene for endogenous expression of the bnAb 10-1074...Future studies will assess whether transplanting higher numbers of engineered HSPC will result in a larger fraction of mice expressing bnAb. These results will guide in vivo engineering approaches and help predict the target editing levels necessary for clinically relevant outcomes."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD34 • IGH • PTPRC • SDC1

Genotypic susceptibility to broadly neutralizing antibodies and fostemsavir of transmitted viruses, and evolution over time in the French acute HIV infection PRIMO cohort (EACS 2025) - "Method : We analyzed 191 sequences from participants in the acute infection French ANRS PRIMO cohort, over 3 decades (1988–2022), using sequence-based algorithms to predict susceptibility to teropavimab (3BNC117), zinlirvimab (10-1074) and entry inhibitors (fostemsavir, maraviroc). Conclusions : These findings underscore the importance of continuous surveillance of transmitted viruses to therapies targeting HIV-1 Env. Integrating phenotypic assessment with genotypic surveillance to refine resistance prediction models will also be important for predicting susceptibility, as well as the correlation with clinical efficacy in ongoing trials."

Human Immunodeficiency Virus • Infectious Disease • CD4

Long-term clinical, immunologic, and viral reservoir outcomes in children treated with VRC01LS and 10-1074 monoclonal antibodies in the Tatelo Study. (PubMed, Clin Infect Dis) - "There was no long-term impact on safety, clinical, immunologic, or virologic outcomes after bNAb-only treatment, including for children who rebounded during the intervention. These findings support further bNAb treatment trials in children."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pediatrics • CD4

Transient rapamycin treatment avoids unwanted host immune responses toward AAV-delivered anti-HIV antibodies. (PubMed, Nat Commun) - "Long-term delivery of broadly neutralizing antibodies (bnAbs) using adeno-associated virus (AAV) vector is a promising approach for both the prevention and treatment of HIV infection. Use of the agent in monkeys results in 12 of 15 successful deliveries of the bnAbs 3BNC117, 10-1074, and PGT145 following drug cessation across all animals. The results of this 5-monkey trial lend strong support to continuing studies in SHIV-infected monkeys and use of this approach in humans for potential worldwide use."

Journal • Human Immunodeficiency Virus • Infectious Disease

HIVACAR: Evaluating a Combination of Immune-based Therapies to Achieve a Remission of HIV Infection (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Judit Pich | N=12 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • IO biomarker • Trial withdrawal • Human Immunodeficiency Virus • Infectious Disease • CD4

Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies. (PubMed, bioRxiv) - "We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different in vivo escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone."

Journal • Human Immunodeficiency Virus • Infectious Disease

HIV-specific T-cell responses in suppressed people with HIV-1 receiving lenacapavir, teropavimab, and zinlirvimab (IAS-HIV 2025) - P1 | "Small increases in these responses were observed when the broadly neutralizing antibodies (bNAbs) 3BNC117 and 10-1074 were dosed during analytical treatment interruption or at ART initiation. Lack of increase from baseline in HIV-specific T-cell response following LEN+TAB+ZAB treatment in VS PWH suggests virologic suppression by LEN+TAB+ZAB did not increase viral antigen expression, which may have limited expansion of HIV-specific T-cells. This has implications for HIV-1 cure studies if greater antigen exposure if required for increased HIV-specific T-cell responses after bNAb administration."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

The Immunogenicity of AAV-Encoded HIV-1 bNAbs in Rhesus Macaques Is Unaffected by a Short Course of the Immunomodulator CTLA4Ig. (PubMed, AIDS Res Hum Retroviruses) - "Six rhesus macaques (RMs) were treated intramuscularly with AAV-1 vectors encoding "rhesusized" (rh) versions of the bNAbs 3BNC117 (IgG1) and 10-1074 (IgG2). In conclusion, a short course rh-CTLA4Ig did not significantly reduce the immunogenicity of AAV-encoded bNAbs in RMs. Although our study was not powered to detect marginal effects, robust improvements in AAV-driven expression of hypermutated HIV-1 bNAbs may require combination approaches, such as multiple co-stimulation blockers, pharmacological immunosuppression, and/or muscle-specific promoters."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD28 • CD4 • CD80 • CD86

Proviral genotype and phenotype as predictors of broadly neutralizing antibody susceptibility (IAS-HIV 2025) - "The utility of PT and GT testing in the Tatelo Study was bNAb dependent. PT susceptibility testing was associated with treatment outcome for 10-1074, and GT testing aligned with the PT results. Neither PT nor GT testing proved useful for VRC01LS, but only few specimens showed preexisting susceptibility."

Human Immunodeficiency Virus • Infectious Disease

Characterization and Optimization of AAV Transgene Cassettes Expressing HIV-1 Broadly Neutralizing Antibody 10-1074 for AAV9-Mediated expression in Non-Human Primates (ASGCT 2025) - "Our study demonstrates that AAV9 delivery of 10-1074, combined with PD-L1 expression, effectively achieves sustained antibody expression and potency while minimizing ADA responses, key requirements for successful HIV-1 therapy. The incorporation of WPRE significantly enhanced transgene expression, with the CBA + WPRE construct achieving the highest expression levels in NHPs. These findings highlight the importance of promoter and enhancer selection in optimizing therapeutic antibody expression and support further development of AAV-based strategies for HIV-1 treatment."

IO biomarker • Human Immunodeficiency Virus • Infectious Disease • PD-L1

Regulation of rAAV transgene expression using nanoparticle-delivered Cre-recombinase protein (ASGCT 2025) - "Lastly, we evaluated our rAAV transgene cassette designs expressing the HIV-1 bNAb 10-1074 in mice that were treated with nanoparticles delivering Cre... Our study demonstrates that nanoparticles provide an efficient system to deliver functional Crerecombinase protein into cells transduced with rAAV cassettes engineered with LoxP sites resulting in a substantial decrease of transgene expression in vitro. Additionally, we conclude that rAAV cassettes containing strategically placed LoxP sites do not interfere with transgene expression in vitro or in vivo. Disease Focus of Abstract:HIV"

Gene Therapies • Human Immunodeficiency Virus • Infectious Disease

AAV-vectored PD-L1 Co-Expression as a Strategy to Enhance AAV-Delivered bNAb Efficacy (ASGCT 2025) - " Five groups of six rhesus macaques each received the following vectors: 1) AAV9.PD-L1; 2) AAV9.10-1074; 3) AAV9.PD-L1 and AAV9.10-1074; 4) AAV9.3BNC117; and 5) AAV9.PD-L1 and AAV9.3BNC117. These studies suggest that co-expression of PD-L1 at the site of administration reduces the host immune response to an AAV-expressed transgene in rhesus macaques. We propose that our vectored PD-L1 co-expression strategy can facilitate the sustained expression of other viral-vectored transgenes. Disease Focus of Abstract:HIV"

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • PD-1 • PD-L1