Biology subjects

Guedj, J.

Publications and source records attributed to Guedj, J..

11 recordsLinked to original sources

bioRxiv2026

Modeling how memory CD8 T cells can elicit post-treatment control of HIV infection

While most people living with HIV suffer progressive disease following cessation of antiretroviral therapy, a small fraction elicits lasting post-treatment control. Understanding the mechanisms underlying this control is key to devising effective HIV remission strategies. Although recent studies implicate memory CD8 T cells, how these cells establish lasting viremic control remains unknown. Here, we combine mathematical modeling and analysis of data from SIV-infected non-human primates to elucidate the underlying mechanisms. We recognized that sustained antigenic stimulation leads to heritable epigenetic remodeling of the CD8 T cell pool, impairing memory cell survivability. Antiretroviral therapy rapidly suppresses viremia, thereby arresting antigenic stimulation and preserving memory potential. The greater this preservation is, the better would be the memory recall response following viral rebound post-treatment. Our mathematical model based on this hypothesis predicts that post-treatment control is an alternative steady state to progressive infection, realized by strong memory-driven recall responses. Our model fits longitudinal virological data spanning the pre-, during-, and post-antiretroviral treatment phases of infection, and recapitulates the outcomes of progressive disease and long-term remission realized, the latter predominantly with early treatment initiation. It shows, consistently with data, that memory CD8 T cells could drive post-treatment control independently of the size of the latent reservoir, explaining how such control may be realized more widely than estimated with prevalent hypotheses. Our model further explains the existence of a window of treatment initiation times that maximizes the chances of post-treatment control. Finally, model predictions inform interventions targeting memory CD8 T cells for HIV remission.

immunology↗

bioRxiv2025

The analysis of a large dataset of PCR-test results in the community reveals the impact of age, variants and vaccination status on SARS-CoV-2 viral dynamics

The COVID-19 pandemic has shown the value of large-scale community PCR tests for epidemic surveillance, but the viral load measurements they provide have seldom been exploited to reconstruct within-host trajectories. Because these data are collected for diagnostic rather than research purposes, they are characterized by sparse longitudinal follow-up, heterogeneous sampling, and missing metadata, raising uncertainty about their usefulness to reconstruct with-host viral dynamics. We first conducted a simulation study to assess the feasibility of estimating the viral dynamics patterns from such datasets. Across multiple scenarios replicating realistic sampling patterns, we found that peak viral load and clearance time could be estimated with good accuracy, although uncertainty tended to be underestimated. Parameters driving early viral kinetics, e.g. incubation and proliferation time, were mostly estimated with poor precision, as most community tests are conducted after symptom onset, later in infection. We then applied this framework to a large dataset of 322,218 PCR tests associated with symptomatic SARS-CoV-2 infections in France between July 2021 and March 2022, encompassing both Delta-variant circulation and the emergence of first Omicron variants. We quantified the effects of age, vaccination, and variants on viral load trajectories. Age [≥]65 years was consistently associated with longer clearance time, extending the duration of detectable viral load by 2 to 6 days. Vaccination shortened the clearance time by 2 to 4 days but had minimal impact on peak viral load. Infections by Omicron-variants were associated with a lower peak viral load and shorter clearance times compared with pre-Omicron (Delta) infections. Thus, community PCR tests can be leveraged to identify key parameters of viral dynamics. As multiplex PCR testing becomes increasingly widespread, establishing robust frameworks for data collection, sharing, and privacy protection will be essential to support the use of these data. Author SummaryIn this study, we explored whether viral load data collected routinely in community laboratories can help us understand how factors like age, vaccination, and viral variant influence the course of infection. These data, collected for diagnostic purposes rather than research, are large but often incomplete, with most individuals tested only after the time of symptoms onset. We first used simulations to assess whether, despite these limitations, key aspects of viral dynamics can be reliably estimated. We then applied our approach to millions of test results collected in France during periods dominated by Delta and Omicron variants. We found that older age was consistently associated with longer infection duration, while vaccination reduced the time the virus remained detectable without affecting peak viral levels. Omicron infections were generally associated with lower peak viral load and somewhat faster clearance than pre-Omicron infections. Overall, our work demonstrates that community testing data, can provide valuable insights into viral dynamics and help monitor the effects of new variants or interventions. As multiplex tests become more common, facilitating and improving data collection, sharing, and privacy protection will be essential to make the most of these resources in future outbreaks.

systems biology↗

bioRxiv2025

Dynamics of interactions between three major respiratory pathogens in reconstituted human epithelium

Respiratory viral coinfections pose a substantial global health burden, yet the underlying virus-virus interactions remain incompletely understood. Here, we systematically examined the interplay among influenza A virus (IAV), SARS-CoV-2, and respiratory syncytial virus (RSV) using a reconstituted human airway epithelium model. We monitored viral replication dynamics and host transcriptional responses under both simultaneous and sequential infection conditions. Our results reveal complex, asymmetric interactions strongly influenced by infection timing and sequence. IAV exerted a pronounced inhibitory effect on SARS-CoV-2, mediated mainly by a robust type III interferon response. However, transient early enhancement of SARS-CoV-2 by IAV and subsequent bidirectional inhibition were also observed. Transcriptomic profiling identified coinfection-specific gene expression signatures enriched for metabolic and cell death pathways. In IAV-RSV coinfections, IAV generally suppressed RSV replication; strikingly, prior RSV infection significantly enhanced subsequent IAV replication, potentially through RSV-induced cellular remodeling or syncytia formation. Overall, host responses to coinfection were integrated and non-additive, with distinct transcriptional programs suggesting activation of unique cellular pathways beyond canonical antiviral responses. Together, these findings highlight the pivotal role of innate immunity and the order of infection in determining the outcome of respiratory viral coinfections, providing mechanistic insights with implications for clinical management and epidemic modeling. Author SummaryRespiratory viruses often circulate simultaneously; however, their interactions within the same host remain poorly understood. We used a reconstituted human airway epithelium model to examine coinfections involving influenza A virus (IAV), SARS-CoV-2, and respiratory syncytial virus (RSV). Our findings reveal that these viruses do not simply compete or coexist: their interactions are dynamic, asymmetric, and highly dependent on the order in which infections occur. IAV generally suppresses SARS-CoV-2 replication through a strong type III interferon response, although brief early enhancement and later mutual inhibition can occur. Transcriptomic profiling reveals that coinfection triggers a complex array of host responses, including alterations in metabolic and cell-death pathways. In IAV/RSV coinfections, IAV consistently inhibits RSV; however, prior RSV infection markedly boosts subsequent IAV replication--likely due to RSV-induced cellular remodeling, such as syncytia formation. These transcriptional signatures point to altered cell adhesion and motility as key features of such interactions. Overall, our results demonstrate that innate immunity and the sequence of infection shape coinfection outcomes in non-additive ways, driving distinct cellular responses beyond classical antiviral pathways. Understanding these mechanisms is essential for improving clinical management and guiding the development of targeted antiviral strategies.

microbiology↗

bioRxiv2025

Late treatment initiation leads to reduced antiviral potency

The timing of initiation is critical in antiviral treatment and viral dynamic (VD) modeling is a powerful tool to study the within-host viral load changes and evaluate antiviral treatment effects using mathematical equations. Previous simulation studies have shown that early treatment initiation is critical to maximize the therapeutic response in antiviral treatment in an acute viral infection such as influenza and SARS-CoV-2. A recent experimental study demonstrated that late therapy initiation can lead to diminished antiviral potency. However, most VD model simulations with varying treatment initiation time accounted only for the effect of initiation condition (i.e., state of different cell populations when the therapy started), the loss of drug potency has been under-investigated. This may overestimate the antiviral effect, potentially resulting in suboptimal dose selection. To this end, we aimed to characterize relationship between the drug potency (EC50) and the timing of drug addition, using nirmatrelvir and GS-441524 against SARS-CoV-2 as an example. Viral load data were obtained from in vitro experiments with various drug concentrations and treatment initiated between 0 to 3 days post infection. EC50 values were fitted for each treatment initiation group and were found to vary with the timing of treatment initiation in both drugs. Also, a VD model with time-varying EC50 provided better fits than a constant EC50 model (BIC = 1667.90 vs. 1677.84). Further simulations also indicated that a constant EC50 model overestimated the antiviral efficacy when treatment started late. These findings highlighted the importance of considering EC50 shift when optimizing dosage regimens for patients presenting late.

pharmacology and toxicology↗

bioRxiv2024

Spatial dynamics of peripheral and central nervous system infection by an interferon-inducing neuroinvasive virus

Organ-to-organ dissemination of viruses is a critical feature of host-virus interactions. In particular, neuroinvasive viruses are able to enter the central nervous systems (CNS), which may result in death or permanent neurological impairment. The complex mechanisms underpinning this spread are poorly understood, as they depend on a variety of parameters, including initial site of entry, route of access to the CNS, and immune responses. To better understand these phenomena, we analyzed the spatial dynamics of Sindbis virus (SINV) dissemination in transparent zebrafish larvae. Using fluorescent reporter viruses, we observed that SINV readily invaded the CNS after inoculation at various peripheral sites. From tail muscle, the virus used dorsal root ganglia (DRG) sensory neurons as a gateway to the spinal cord and further propagation to the brain. While peripheral infection was systematically transient, due to the key protective role of the strong and rapid type I interferon (IFN) response, CNS infection was persistent and more variable. Within the CNS, viral dissemination resulted both from long-distance axonal transport and short distance shedding, and IFN response was local, while it was systemic in the periphery. A mathematical model was built on this quantitative imaging foundation, that provided additional insight on the parameters of this infection, such as the rate of new virion production, estimated around 1 to 2 infective virions per productively infected cell per hour; the occurrences of CNS entry events, which was 2 to 3 per larva; or the impact of the IFN response, which did not only prevent new infections but accelerated the death of infected cells.

microbiology↗

bioRxiv2023

Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control. For each macaque, we considered, in addition to the canonical in vivo plasma viral load and SIV DNA data, longitudinal ex vivo measurements of the virus suppressive capacity of CD8 T-cells. Available mathematical models do not allow analysis of such combined in vivo-ex vivo datasets. By explicitly modeling the ex vivo assay and integrating it with in vivo dynamics, we developed a new framework that enabled the analysis. Our model fit the data well and estimated that the recruitment rate and/or maximal killing rate of CD8 T-cells was up to 2-fold higher in controllers than non-controllers (p=0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with virus control (Spearmans {rho}=- 0.51; p=0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T-cells as a predictor of natural control. Furthermore, simulating a large virtual population, our model quantified the minimum capacity of this early CD8 T-cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T-cells in the natural control of HIV infection and has implications for remission strategies.

microbiology↗

bioRxiv2022

Impact of variants of concern on SARS-CoV-2 viral dynamics in non-human primates.

The impact of variants of concern (VoC) on SARS-CoV-2 viral dynamics remains poorly understood and essentially relies on observational studies subject to various sorts of biases. In contrast, experimental models of infection constitute a powerful model to perform controlled comparisons of the viral dynamics observed with VoC and better quantify how VoC escape from the immune response. Here we used molecular and infectious viral load of 78 cynomolgus macaques to characterize in detail the effects of VoC on viral dynamics. We first developed a mathematical model that recapitulate the observed dynamics, and we found that the best model describing the data assumed a rapid antigen-dependent stimulation of the immune response leading to a rapid reduction of viral infectivity. When compared with the historical variant, all VoC except beta were associated with an escape from this immune response, and this effect was particularly sensitive for delta and omicron variant (p<10-6 for both). Interestingly, delta variant was associated with a 1.8-fold increased viral production rate (p=0.046), while conversely omicron variant was associated with a 14-fold reduction in viral production rate (p<10-6). During a natural infection, our models predict that delta variant is associated with a higher peak viral RNA than omicron variant (7.6 log10 copies/mL 95% CI 6.8 - 8 for delta; 5.6 log10 copies/mL 95% CI 4.8 - 6.3 for omicron) while having similar peak infectious titers (3.7 log10 PFU/mL 95% CI 2.4 - 4.6 for delta; 2.8 log10 PFU/mL 95% CI 1.9 - 3.8 for omicron). These results provide a detailed picture of the effects of VoC on total and infectious viral load and may help understand some differences observed in the patterns of viral transmission of these viruses.

microbiology↗

bioRxiv2021

Combination of in vivo phage therapy data with in silico model highlights key parameters for treatment efficacy

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactions in vivo. Here we developed a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain of Escherichia coli. The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.

microbiology↗

bioRxiv2020

Favipiravir and severe acute respiratory syndrome coronavirus 2 in hamster model

Despite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we used a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment was initiated before or simultaneously to infection, favipiravir had a strong dose effect, leading to dramatic reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlated with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. The antiviral efficacy observed in this study was achieved with plasma drug exposure comparable with those previously found during human clinical trials and was associated with weight losses in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.

microbiology↗

bioRxiv2020

Modeling SIV kinetics supports that cytotoxic response drives natural control and unravels heterogeneous populations of infected cells

SIVmac251-infected Mauritius cynomolgus macaques presenting a M6 MHC haplotype or challenged with a low inoculum dose by mucosal route are models for natural HIV control. Here we characterized by modeling the dynamics of plasma SIV-RNA and of SIV-DNA in blood cells of 16 macaques of the ANRS SIC study. SIV-RNA kinetics was best fitted using a model where the cytotoxic immune response progressively mounted up and reduced actively infected cells half-life (t1/2) from 5.5 days early on to about 0.3 days. The model predicted that the control was achieved in animals able to mount an effective immune response within three months, and this was corroborated by the longitudinal analysis of the CD8+ T-cell antiviral activity measured ex vivo. The control of SIV-RNA was accompanied in parallel by a slow and biphasic decline of SIV-DNA. This unravels the presence of at least two compartments of non-actively infected cells that are not rapidly eliminated by the immune system, one with a rapid turnover rate (t1/2=5.1 days) and predominant as long as SIV-RNA levels are still large, and one with a slow turnover (t1/2=118 days) consistent with the half-life of memory T-cells, and only visible when control is achieved. In summary, our analysis suggests that the establishment of an efficient CD8+ T-cell response in the first three months of the infection, and that progressively increases overtime is key to achieve SIV-RNA control in this model. Frequent SIV-DNA quantifications allowed identifying that most cells infected after viral peak have a short t1/2 but do not contribute significantly to viral production. One sentence summaryModeling viral dynamics in SIV natural controller macaques predicts that viral control is primarily driven by the capability to establish an efficient cytotoxic response and the viral decline during control unravels distinct compartments of infected cells.

microbiology↗

bioRxiv2019

Optimal maturation of the SIV-specific CD8+ T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study

Highly efficient virus-specific CD8+ T-cells are associated with immune control of HIV infection, but it remains unclear how these cells are generated and maintained over time. We used a macaque model of spontaneous control of SIVmac251 infection to monitor the development and evolution of potent antiviral CD8+ T-cell responses. SIV-specific CD8+ T-cells emerged during primary infection in all animals. However, the ability of CD8+ T cells to suppress SIV replication was low in early stages but increased after a period of maturation, temporally linked with the establishment of sustained low-level viremia in controller macaques. SIV-specific CD8+ T-cells with a central memory phenotype expressed higher levels of survival markers in controllers versus non-controllers. In contrast, a persistently skewed differentiation phenotype was observed among central memory SIV-specific CD8+ T-cells in non-controllers since primary infection, typified by relatively high expression levels of T-bet. Collectively, these data show that the phenotype of SIV-specific CD8+ T-cells defined early after SIV infection favor the gain of antiviral potency as a function of time in controllers, whereas SIV-specific CD8+ T-cell responses in non-controllers fail to gain antiviral potency due to early defects imprinted in the central memory pool.

immunology↗