Biology subjects

Trautmann, L.

Publications and source records attributed to Trautmann, L..

6 recordsLinked to original sources

bioRxiv2026

A Bispecific Biologic That Robustly Reverses HIV-1 and SIV Latency

Antiretroviral therapy suppresses HIV-1 replication but cannot eliminate the latent viral reservoir persisting in memory CD4 T cells. Existing latency reversal candidates have yet to achieve robust viral reactivation at tolerable doses. We engineered T4IL15{triangleup}, a bispecific biologic that selectively delivers IL-15 signaling to memory CD4 T cells, with minimal off-target stimulation. T4IL15{triangleup} reactivated latent virus in 94% (48/51) of clinical samples ex vivo, 75% (15/20) of administrations in HIV-1-infected and ART-suppressed humanized mice, and 100% (6/6) of SIV-infected and ART-suppressed rhesus macaques at doses well tolerated. We also found that off-target stimulation of non-CD4 cells hindered HIV-1 reactivation ex vivo. T4IL15{triangleup} provides a robust reactivation platform that could complement other reservoir-elimination strategies toward an HIV-1 cure.

microbiology↗

bioRxiv2026

Ultrasensitive single-genome sequencing reveals strong purifying selection in acute HIV-1 infection

HIV transmission from one individual to another occurs by one or a small number of virions followed by spread and genetic diversification into a complex quasispecies. To understand the early events in this process, we investigated how HIV-1 genomes diversify within the first two to three weeks after transmission by use of ultra-deep single subgenomic sequencing of over 10,000 plasma RNA genomes in each of a cohort of 15 individuals in acute infection. This approach confirmed transmission of one or a few transmitted/founder (TF) viral lineages and very limited early divergence from the founder sequences. Most observed variants that differed from the TF included single nucleotide changes attributable to HIV-1 reverse transcriptase (RT) error or host APOBEC3G/F activity. Comparing the number of expected versus observed changes after transmission indicated that most de novo mutations do not persist in the virus population, consistent with strong purifying selection. We found little evidence that early diversification is driven by reversions to subtype consensus or by cytotoxic T lymphocyte pressure, although rare multi-mutation lineages suggest occasional influences. Together, these findings indicate that early HIV-1 evolution is influenced by stochastic and host-mediated mutational processes (e.g., APOBEC3G/F) filtered by strong purifying selection. The strong purifying selection observed in the early weeks of HIV-1 infection may provide an opportunity to investigate the potential of new interventions to induce viremic control, such as combinations of broadly neutralizing antibodies, cellular immunotherapy, or mRNA therapeutic vaccination.

microbiology↗

bioRxiv2026

Unique CD8+ T Cell Populations Expand during ART and Predict Delayed HIV-1 Rebound

Antiretroviral therapy (ART) suppresses HIV-1 replication but does not eliminate the latent reservoir, resulting in viral rebound with variable kinetics after treatment interruption. How the immune cell states established during ART influences timing of rebound is not fully understood. In this study, we analyzed 111 participants across multiple cohorts, with 188 single-cell multiomic samples generated and integrated for joint analysis. Longitudinal profiling of peripheral blood mononuclear cells from individuals with acute HIV-1 infection on ART, spanning early infection through sustained therapy and pre-analytical treatment interruption, revealed that time to viral rebound was driven not by global changes in immune composition but by dynamic transcriptional programs within CD8+ T cells. During ART, there was a dramatic expansion of a unique cluster of poised naive CD8+ T cells, with a distinct immune state positioned upstream of stem-like memory CD8+ T cells along a cell differentiation continuum. The differential abundance of this poised naive CD8+ T cell population was enriched in participants with delayed rebound and showed strong predictive power for discriminating time to rebound. Mechanistically, the poised naive CD8+ T cells exhibited features of a precursor phenotype of stem-like memory CD8+ T cells, and showed activation of the TNF-NF-{kappa}B signaling pathway and increased chromatin accessibility at AP-1 motifs. Notably, both poised naive CD8+ T cells and stem-like memory CD8+ T cells were consistently enhanced during ART in both acute and chronic infection. In participants who received investigational therapeutic vaccination, the dominant predictive signal shifted downstream along the differentiation trajectory, with stem-like memory CD8+ T cells emerging as the primary determinant of delayed rebound. Together, these findings identify a dynamic CD8+ T cell state continuum as a central determinant of HIV-1 rebound, even in the absence of antigen-specificity, where ART establishes a predictive poised naive state that can be further leveraged by vaccination to enhance protective stem-like memory responses.

immunology↗

bioRxiv2025

Sustained learned immunosuppression could not prevent local allergic ear swelling in a rat model of contact hypersensitivity

Taste-immune associative learning has been shown to mimic immunopharmacological responses. Conditioned pharmacological effects may therefore be considered as controlled drug dose reduction strategy to maintain treatment efficacy. Against this background, the present study applied an established taste-immune associative learning protocol to a rat model of hapten-induced contact hypersensitivity. After repeated pairings of a saccharin taste (conditioned stimulus, CS) with injections of the immunosuppressant cyclosporine A (CsA, unconditioned stimulus, UCS), animals were sensitized with the hapten. Retrieval started by presenting the CS together with sub-effective doses of CsA. This procedure preserved a conditioned suppression of splenic cytokine production. Compared to full dose treated animals, conditioned effects were neither observed in draining lymph nodes nor did it prevent ear swelling. These findings suggest that local allergic reactions in sensitized animals were most likely too strong to be responsive to the learned immunosuppressive effects. Additionally, symptoms such as itch may be more suited as readout parameter since it better reflects patients disease burden. The present study reaffirms that learned immunopharmacological effects can be preserved using a memory-updating approach. It also emphasizes the need to further explore the usability of associative learning protocols in clinical contexts in order to address disease-specific symptoms more effectively.

animal behavior and cognition↗

bioRxiv2022

A small molecule RIG-I agonist serves to adjuvant broad multifaceted influenza virus vaccine immunity

Retinoic acid-inducible gene I (RIG-I) is essential for activating host cell innate immunity to regulates the immune response against many RNA viruses. We identified a small molecule compound, KIN1148, that directly binds RIG-I to drive IRF3activation to impart the expression of IRF3-target genes, including specific immunomodulatory cytokines and chemokines. KIN1148 does not lead to ATPase activity or compete with ATP for binding but activates RIG-I to induce antiviral gene expression programs distinct from type I interferon (IFN) treatment. When administered in combination with a vaccine against influenza A virus (IAV), KIN1148 induces both neutralizing antibody and broadly cross-protective IAV-specific T cell responses compared to vaccination alone, which induces comparatively poor responses. This robust KIN1148-adjuvanted immune response protects mice from lethal H1N1 and H5N1 IAV challenge. Importantly, KIN1148 also augments human CD8+ T cell activation. Thus, we have identified a small molecule RIG-I agonist that serves as an effective adjuvant in inducing non-canonical RIG-I activation for induction of innate immune programs that enhance adaptive immune protection of antiviral vaccination. SummaryHemann, et. al. identify a small-molecule RIG-I agonist (KIN1148) that directly binds RIG-I for non-canonical activation and adjuvants pandemic and avian influenza virus vaccination. KIN1148 augments broadly neutralizing antibody and T cell responses in mice and enhances human DC maturation and CD8+ T cell activation.

immunology↗

bioRxiv2022

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

Upon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We analyzed productively and latently infected cells in blood and lymphoid tissue from individuals in acute infection. The phenotype of productively infected cells rapidly evolved with time and differed between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded/disseminated cells, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells in blood and lymph nodes and latently infected cells are generated simultaneously. One-Sentence SummaryHIV initially infects phenotypically and clonotypically distinct T cells and establishes a latent reservoir concomitantly.

microbiology↗