IMMU Subgroup Contributed Talks

Daniel Rüdiger

Max Planck Institute Magdeburg

"The secrets of “OP7”, an influenza DIP: mathematical model, impact of mutations and antiviral mechanisms"

Defective interfering particles (DIPs) are mutated, replication-incompetent virions that can inhibit their corresponding standard virus (STV). Previous studies have shown the effectiveness of DIPs against various virus species, highlighting them as promising broad-spectrum antivirals. OP7, an influenza DIP with 37 nucleotide substitutions in its segment 7 (S7) vRNA, has been found to suppress STV replication more effectively than conventional DIPs. However, the effects of these mutations on the replication of OP7 and its mechanism of interference with the STV remained unclear. In this study, we investigated the infection dynamics during a coinfection of influenza STV and OP7 in cell culture. We monitored the dynamics of viral RNAs, assessed viral protein levels, and determined virus titers. With these experimental results, we developed a mathematical model to simulate the coinfection of STV and OP7. Subsequently, we used this model to explore various hypotheses about the impact of mutations on virus replication and to predict the suppression of STV by OP7 in passaging experiments. In vitro experiments show that S7-OP7 surpasses the levels of all STV genome segments. Model simulations suggest this is induced by a significantly increased rate of replication, attributed to mutations in S7-OP7 inducing a “superpromoter”. Additionally, simulations predicted a notable reduction in viral mRNA transcription for S7-OP7, which was later validated experimentally. Moreover, we deduce that the M1 protein derived from S7-OP7 mRNA is likely defective. Lastly, the model accurately predicts the spread of OP7 and the suppression of STV in infected cell cultures over multiple passages under various initial conditions. In summary, we developed a mathematical model that enables a thorough examination of STV and OP7 coinfection, improves our understanding of DIP interference mechanisms, and supports the development of antiviral therapies.

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Ying Xie

Kyoto University

"Antihistamine Efficacy in Relation to the Morphology of Skin Eruptions in Chronic Spontaneous Urticaria"

Chronic spontaneous urticaria (CSU) is a persistent skin disorder characterized by red, itchy eruptions of various shapes, known as wheals. These wheals appear and disappear daily, persisting for months or even decades, and severely impact patients' quality of life. The standard treatment for CSU primarily consists of second-generation H1 antihistamines, often administered at higher-than-usual doses. However, approximately 30% of patients remain symptomatic despite these conventional therapies. On the other hand, our previous mathematical modeling and clinical studies have identified five distinct types of wheal shapes through the development of clinical criteria for eruption geometry (EGe Criteria) and have shown how the characteristics of each wheal type are involved in the pathophysiology of CSU. These findings suggest that CSU may be classified into five medical subtypes based on wheal morphology. Thus, in this study, we explore the effectiveness of antihistamines based on wheal shape. We first evaluate the efficacy of antihistamines in silico using three key measures: wheal area, itching severity, and wheal expansion dynamics, across the five identified wheal types. Additionally, we validate some of our theoretical observations using clinical data from patients. By elucidating the relationships among the key networks involved in CSU pathophysiology, wheal morphology, and drug efficacy, we can enhance the development of more accurate diagnostic tools and treatment strategies in clinical settings.

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Madeleine Gastonguay

Institute for Computational Medicine, Johns Hopkins University

"Viral rebound kinetics following single and combination immunotherapy for HIV/SIV"

Combination antiretroviral therapy (ART) can treat but not cure HIV, motivating the development of therapies that stimulate the immune system to control or eliminate infection. Two such immunotherapies- a TLR7 agonist and a therapeutic vaccine - were previously tested in SIV-infected rhesus macaques. Animals received ART alone or with concurrent single or combination immunotherapy, and viral rebound was monitored after treatment interruption. Many treated animals exhibited altered rebound kinetics, and a subset achieved either complete viral suppression or immune control after an initial rebound. However, the mechanisms driving these effects are unknown: do these therapies deplete the latent reservoir or enhance antiviral immunity, and do they act synergistically? To investigate the effects of immunotherapy, we built a mathematical model of viral dynamics incorporating latent cell reactivation and a generalized immune response. We confirmed the model could reproduce the range of rebound trajectories seen in the data, and examined whether parameters could be reliably estimated from the available data. Using nonlinear mixed-effects modeling, we quantified interindividual variability and identified significant differences in model parameters between treatment groups. Our results indicate that the vaccine alone reduces latent virus reactivation and enhances immune response avidity. The TLR7 agonist, when administered after late ART initiation, increases target cell availability and reduces the latent reservoir. We found that regardless of ART initiation, the two therapies act synergistically to further enhance immune response avidity. Immune avidity appeared to increase with later ART initiation, although whether this effect is specific to TLR7 treatment is unclear. Our model provides mechanistic insight into immunotherapeutic control of viral rebound and can be adapted to predict their impact in controlling HIV, guiding future therapeutic design and clinical trials.

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