Criado, M. F. | Search bioRxiv

bioRxiv2025

Informing antiviral effectiveness for influenza A andSARS-CoV-2 by quantifying within-host interaction betweentransmission and immunity

Antiviral therapies are among the most effective pharmaceutical interventions in treatment of a variety of viral pathogens. To optimize the antiviral effectiveness it is crucial to characterize the relationship between multiple cellular modes of antiviral action and the complex response of the hosts innate immune system relative to the within host dynamics of a proliferating virus. Since their introduction in 1968 and 2019, Influenza A virus (IAV) H3N2 and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), respectively, have caused unprecedented damage on the public health infrastructure globally. In addition to the substantial burden of morbidity and mortality around the world, both viruses have the potential of undergoing evolution leading to antigenic escape from the prevailing interventions. These biological characteristics advocate for urgent development of effective antivirals for the treatment of IAV and SARS-CoV-2. In this multi-stage study, we develop a suite of within-host models encompassing a number of hypotheses regarding virus-specific innate host functional responses and their impacts on the proliferation of IAV H3N2 and SARS-CoV-2 viruses. We use likelihood-based statistical inference to confront these hypotheses with infection data on IAV H3N2 and SARS-CoV-2 from infection experiments in ferrets. Upon identifying the best-fitting model of within-host dynamics, we can quantify the potential impact of antiviral drug therapy as a function of effectiveness and timing of initiation. We find significant mechanistic differences between the infection dynamics of H3N2 IAV and SARS-CoV-2 and associated model parameters. The treatment consequences of these differences are that SARS-CoV-2 is harder to control with antivirals, requiring earlier initiation and a more effective drug. Author summaryAntiviral drugs are prophylactic chemical agents that are used to contain several viral infections. Influenza A H3N2 virus (H3N2) and Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) are very important viral pathogens that have caused unprecedented, global public health damage in the recent times. This makes development of antiviral drugs crucial along with other pharmaceutical prophylactics like vaccination. To optimize the pathogen specific effectiveness, however, it is necessary to simultaneously explore the relationship among the intra-host viral kinetics, immune dynamics and modes of antiviral action. In this article we theoretically analyze antiviral action of a drug in union with effect of the hosts innate immune system in containing infections of SARS-CoV-2 and H3N2 in infection experiments with ferrets. We find fundamental differences in the requisite antiviral effectiveness which, we posit, is due to substantially different inter-cellular proliferation potential between the two viruses.

ecology↗

bioRxiv2023

A general computational design strategy for stabilizing viral class I fusion proteins

Many pathogenic viruses, including influenza virus, Ebola virus, coronaviruses, and Pneumoviruses, rely on class I fusion proteins to fuse viral and cellular membranes. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more favorable and stable postfusion state. An increasing amount of evidence exists highlighting that antibodies targeting the prefusion conformation are the most potent. However, many mutations have to be evaluated before identifying prefusion-stabilizing substitutions. We therefore established a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. As a proof of concept, we applied this principle to the fusion protein of the RSV, hMPV, and SARS-CoV-2 viruses. For each protein, we tested less than a handful of designs to identify stable versions. Solved structures of designed proteins from the three different viruses evidenced the atomic accuracy of our approach. Furthermore, the immunological response of the RSV F design compared to a current clinical candidate in a mouse model. While the parallel design of two conformations allows identifying and selectively modifying energetically less optimized positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. We recaptured many approaches previously introduced manually for the stabilization of viral surface proteins, such as cavity-filling, optimization of polar interactions, as well as postfusion-disruptive strategies. Using our approach, it is possible to focus on the most impacting mutations and potentially preserve the immunogen as closely as possible to its native version. The latter is important as sequence re-design can cause perturbations to B and T cell epitopes. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.

microbiology↗