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Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections.

A mathematical model of the human immunodeficiency virus Type 1 (HIV-1) life cycle in CD4 T cells was constructed and calibrated. It describes the activation of the intracellular Type I interferon (IFN-I) response and the IFN-induced suppression of viral replication. The model includes viral replication inhibition by interferon-induced antiviral factors and their inactivation by the viral proteins Vpu and Vif. Both deterministic and stochastic model formulations are presented. The stochastic model was used to predict efficiency of IFN-I-induced suppression of viral replication in different initial conditions for autocrine and paracrine effects. The probability of virion excretion for various MOIs and various amounts of IFN-I was evaluated and the statistical properties of the heterogeneity of HIV-1 and IFN-I production characterised.

Mathematical modelling of infection processes in cells is of fundamental interest. It helps to understand the SARS-CoV-2 dynamics in detail and can be useful to define the vulnerability steps targeted by antiviral treatments. We previously developed a deterministic mathematical model of the SARS-CoV-2 life cycle in a single cell. Despite answering many questions, it certainly cannot accurately account for the stochastic nature of an infection process caused by natural fluctuation in reaction kinetics and the small abundance of participating components in a single cell. In the present work, this deterministic model is transformed into a stochastic one based on a Markov Chain Monte Carlo (MCMC) method. This model is employed to compute statistical characteristics of the SARS-CoV-2 life cycle including the probability for a non-degenerate infection process. Varying parameters of the model enables us to unveil the inhibitory effects of IFN and the effects of the ACE2 binding affinity. The simulation results show that the type I IFN response has a very strong effect on inhibition of the total viral progeny whereas the effect of a 10-fold variation of the binding rate to ACE2 turns out to be negligible for the probability of infection and viral production.

A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular ‘sponges’, stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ∼2400 Gag and ∼120 GagPol by the viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak–strong–moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules.

SARS-CoV-2 infection represents a global threat to human health. Various approaches were employed to reveal the pathogenetic mechanisms of COVID-19. Mathematical and computational modelling is a powerful tool to describe and analyze the infection dynamics in relation to a plethora of processes contributing to the observed disease phenotypes. In our study here, we formulate and calibrate a deterministic model of the SARS-CoV-2 life cycle. It provides a kinetic description of the major replication stages of SARS-CoV-2. Sensitivity analysis of the net viral progeny with respect to model parameters enables the identification of the life cycle stages that have the strongest impact on viral replication. These three most influential parameters are (i) degradation rate of positive sense vRNAs in cytoplasm (negative effect), (ii) threshold number of non-structural proteins enhancing vRNA transcription (negative effect), and (iii) translation rate of non-structural proteins (positive effect). The results of our analysis could be used for guiding the search for antiviral drug targets to combat SARS-CoV-2 infection.

Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections.