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

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

Editing Hematopoietic Stem and Progenitor Cells by Non-Viral Gene Knock-In Produces Anti-HIV Antibody In Vivo (ASGCT 2025) - "To assess anti-HIV antibody expression, we developed a template encoding the broadly neutralizing antibody 10-1074 under the control a B cell-specific promoter, derived from a NHP variable heavy domain...Future work will assess efficacy in a NHP model of simian-HIV infection. Disease Focus of Abstract:HIV"

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

Therapeutic efficacy of AAV-delivered HIV-1 bNAbs to prevent SHIV rebound in rhesus macaques (ASGCT 2025) - "Macaques in the treatment group received AAV9 vectors encoding 10-1074 and 3BNC117 co-delivered with AAV9 vectors encoding PD-L1 administered intramuscularly at 36 weeks post-infection. Our ongoing study reveals that the co-expression 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. Disease Focus of Abstract:HIV"

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

Distinct region-specific neutralization profiles of contemporary HIV-1 clade C against best-in-class broadly neutralizing antibodies. (PubMed, J Virol) - "Env-pseudotyped viruses encoding HIV-1 India clade C env were found to be best neutralized by the V3 glycan-directed bnAbs (10-1074 and BG18) and select CD4 binding site (CD4bs)-directed bnAbs (VRC07, N6, and 1-18); however, they demonstrated significant resistance to V1/V2 apex-directed bnAbs...Notably, the second generation CD4bs bnAbs (VRC07, N6, 1-18) showed neutralization of VRC01- and 3BNC117-resistant viruses but with two- to sevenfold reduced potency compared to the VRC01-sensitive counterparts, likely due to the enrichment of resistance-associated residues observed in loop D. Predictive analysis indicated that the combination of BG18, N6, and PGDM1400 can provide over 95% neutralization coverage of contemporary India clade C at 1 µg/mL (IC80), an observation distinct from that observed with Africa clade C. Our study clearly highlights that both the complementarity of bnAb classes and the regionally relevant HIV-1 forms are important in achieving clinical..."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains. (PubMed, J Virol) - "This study uses pseudoviruses to map all escape mutations for antibodies 10-1074 and 3BNC117 for the Envelope proteins from two different HIV strains. These maps can inform analyses of viral mutations observed in clinical trials and help understand how the escape mutations from these antibodies differ across HIV strains."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Clinical trials of broadly neutralizing monoclonal antibodies in people living with HIV - a review. (PubMed, AIDS Res Ther) - "More recent trials that paired bNAbs with latency-reversing agents or combined multiple bNAbs demonstrated promising results, including delayed viral rebound and enhanced CD8 + T-cell responses. While bNAbs show potential as an adjunct or alternative to ART, obstacles such as viral resistance, high production costs, and scalability must be addressed. Continued research is crucial to developing more potent, durable, and affordable bNAbs for sustainable HIV treatment and potential remission."

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

Combination immunotherapy induces post-intervention control of HIV. (PubMed, Res Sq) - "Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (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 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. 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

Safety, Tolerability, and Efficacy of IL-15 Superagonist (N-803) With and Without Combination Broadly Neutralizing Antibodies to Induce HIV-1 Control During Analytic Treatment Interruption (clinicaltrials.gov) - P1 | N=118 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Active, not recruiting | N=46 ➔ 118

Enrollment change • Enrollment closed • Human Immunodeficiency Virus • Infectious Disease • CD4

Predictive markers for sustained viral suppression on dual bNAbs during ART interruption in children. (PubMed, J Acquir Immune Defic Syndr) - "At the start of bNAb-only treatment, negative qualitative DNA, and especially negative/negative DNA and EIA, have potential to predict maintenance of viral suppression among children on dual bNAbs. HIV RNA target detection below the assay limit did not prove to be a clinically useful biomarker in the visits preceding failure."

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

A Strategy for Durable AAV-Vectored bNAb Expression in Adult Rhesus Macaques (CROI 2025) - "Methods 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. Conclusions We have developed a strategy for sustained bNAb expression in NHPs. This will allow the prophylactic and therapeutic efficacy of AAV-delivered bNAbs to be studied in preclinical NHP models."

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease

Resistance of Inducible, Infectious HIV-1 to Autologous Neutralizing IgG After Long-Term ART (CROI 2025) - "Neutralization assays tested either contemporaneous aNAbs or one of three broadly neutralizing antibodies (bNAbs; VRC01, 10-1074, PGDM1400). Conclusions Our findings demonstrated increased resistance of outgrowth viruses to aNAbs over long-term ART, which was not fully explained by a decline in neutralizing antibody concentrations. This increased resistance may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses, leaving only aNAb-resistant viruses which can contribute to viral rebound."

Human Immunodeficiency Virus • Infectious Disease • CD4

Immune Correlates of Viral Rebound During Broadly Neutralizing Antibody Treatment in Children (CROI 2025) - "Results Of 25 participants aged 2-5 years who received VRC01LS plus 10-1074 dual-bNAb treatment, 11 maintained viral suppression (controllers) and 14 rebounded (rebounders). Conclusions Specific NK cell responses at the beginning of bNAb-only treatment were associated with viral rebound, the kinetics of rebound, and the intact viral reservoir size. HIV-1 specific T cell responses were low in this group of early-treated children and differences could not be identified between controllers and rebounders."

Clinical • Human Immunodeficiency Virus • Infectious Disease • HLA-C • KIR2DL1 • KLRC1