Biology subjects

Relouzat, F.

Publications and source records attributed to Relouzat, F..

8 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↗

bioRxiv2026

Dual blockade of LILRB1 and LILRB2 enhances antiviral immune responses in SIV infection

Restoring effective antiviral immunity remains a major challenge in HIV infection. Among emerging immune checkpoint molecules, the inhibitory receptors LILRB1 and LILRB2 have been proposed as therapeutic targets, yet their in vivo function remains undefined due to the lack of cross-reactive blocking antibodies for relevant preclinical models. To address this, we developed a dual-specific blocking monoclonal antibody, mac20G10, targeting cynomolgus macaque LILRB1 and LILRB2 and assessed its immunomodulatory activity in an SIV model of infection. Pharmacodynamics analyses demonstrated that mac20G10 persisted in circulation and engaged target myeloid cells for up to 14 days without detectable adverse effects. A single administration prior to SIVmac251 infection enhanced early myeloid immune activation, characterized by increased frequencies of CD80+ pDC and CD80+ monocyte/macrophage subsets in blood and lymphoid tissues. These changes were accompanied by increased plasma levels of IFN-{lambda}, IL8, and IL-1RA during acute infection. Although viral replication remained unchanged, mac20G10 treatment promoted the development of SIV-specific memory CD8 T-cell responses. Together, these findings provide in vivo evidence that LILRB1 and LILRB2 function as myeloid immune checkpoints restraining antiviral priming, supporting this pathway as a rational target for combination immunotherapeutic strategies aimed at achieving durable HIV remission during analytic treatment interruption.

immunology↗

bioRxiv2026

Joint mechanistic modeling of viral and antibody responses to vaccines in non-human primates to quantify SARS-CoV-2 mechanistic correlates of protection

In a global SARS-CoV-2 landscape of hybrid immunity resulting from a vaccinated worldwide population and the emergence of new variants able to escape immunity, the identification and quantification of correlates of protection (CoPs) is crucial for the adaptation of next-generation SARS-CoV-2 vaccines. Antibodies and their neutralizing capacity have been identified as reliable mechanistic CoPs. Here, we proposed an original mechanistic model jointly describing viral and antibody dynamics, and their mutual interactions, observed after SARS-CoV-2 infection in non-human primates (NHPs) with distinct immunological backgrounds. From the model, the concentration of neutralizing antibodies being protective against viral infection spreading was derived using the reproduction number. Counterfactual simulations were also performed to better understand and validate immune mechanisms driving immune control. The model was estimated on viral, binding (bAb), and neutralizing (nAb) antibody dynamics, with data collected in 34 naive and convalescent NHPs. Animals were involved in a preclinical study evaluating two next-generation protein-based vaccines targeting the RBD of the Spike protein to CD40-expressing cells, and the original BNT162b2 mRNA vaccine against Delta SARS-CoV-2 infection. Our model validated the functionality of nAb to neutralize viruses as the primary mechanism of protection. An inhibitory antibody concentration against Delta variant of 20 AU/mL was deemed protective against Delta infection in naive animals. Moreover, we showed the strong benefit of hybrid immunity to induce faster and more protective antibody responses pointing out the crucial role of the memory B-cell immune response in viral control. Finally, an additional effect of natural immunity beyond antibodies and enhancing the elimination of infected cells was identified, suggesting the potential role of the T-cell response in viral control. Our model showed the benefit of combining information from both viral and antibody responses to better qualitatively and quantitatively inform on their protective capacity against Delta SARS-CoV-2 infection.

immunology↗

bioRxiv2025

Disease progression is associated with differential neutrophil maturation in Mycobacterium tuberculosis-infected macaques

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is associated with clinical diversity and outcomes ranging from latent TB to active TB with distinct pathophysiologies. However, our understanding of the innate immune mechanisms related to the protection or progression of TB is limited. Among innate immune cells, the role of neutrophils is not fully elucidated, as they have been shown to exhibit both protective and harmful capacities in TB. This duality suggests possible differences in the nature and type of neutrophils present during the infection, generating different effects. We hypothesized that Mtb infection induces changes in neutrophil phenotype and function, influencing the infection outcomes. In order to decipher the link between neutrophils and disease progression, we used a cynomolgus macaque model of human TB. Based on clinical, bacteriological, and positron emission tomography with X-ray computed tomography (PET/CT) scan parameters, animals were stratified into two categories: animals that rapidly progressed to an active form of TB, designated as "fast progressors", and "slow progressors", which include low symptomatic or asymptomatic animals. In this study, we identified transcriptomic signatures of type I interferons and neutrophil degranulation in macaques with fast progression to active TB, which were not observed in animals with slow TB progression. Unsuppervised mass cytometry analysis showed the emergence of blood immature neutrophils (CD101+ CD10-) in fast progressing animals. In addition, circulating neutrophils from infected animals displayed capacities to modulate TNF- production and cytotoxic function of CD8 T cells in a contact-dependent mechanism. In the lungs, neutrophils infiltration in granuloma was higher in fast progressors and specifically located in the lymphocyte-rich region in lesions. These data suggest that specific neutrophil subpopulations are associated with disease progression. Furthermore, these data suggest that neutrophils may modulate CD8 T cells functions, which in turn contribute to the loss of Mtb control and fuel inflammation. AUTHORS SUMMARYMycobacterium tuberculosis (Mtb) infection in humans is associated with a wide range of disease progression, ranging from latent tuberculosis (TB) to active TB. Understanding immune factors leading to the control of the infection or disease progression is essential to identify new biomarkers and targets for host-directed therapies. Innate immunity plays an important role in inflammatory imbalance observed in active TB, among which neutrophils have both beneficial and detrimental roles. Using a macaque model developing a broad range of clinical forms of TB, we seek to understand the links between neutrophils and disease progression. We found that rapid progression to active TB leads to type I interferon signalling and neutrophil activation. In the blood, immature neutrophils were enriched when the disease progressed. In case of severe TB, Neutrophils also infiltrate a specific region of lung TB lesions rich in T lymphocytes, whereas they could modulate CD8 T cells. Our study provides new insights into the role of neutrophils in TB progression.

immunology↗

bioRxiv2023

Optimization of neuromuscular blockade protocols in cynomolgus macaques: monitoring, doses and antagonism

BackgroundNeuromuscular blocking agents (NMBAs) are a crucial component of anaesthesia and intensive care. NMBAs are a family of molecules defined by their ability to compete with acetylcholine for binding to the acetylcholine receptor at the neuromuscular junction. This functional homology relies on the presence of ammonium groups in all NMBAs that, however, display vastly different chemical structures. Among animal models, non-human primates (NHP) are an essential model for a great diversity of human disease models but remain poorly characterized for the effectiveness of the diverse NMBAs. MethodsSeven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anaesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anaesthesia was maintained with isofluorane. Either rocuronium bromine or atracurium besylate was evaluated, with reversal with sugammadex. Monitoring was performed with two devices, TOF-Watch(R) and ToFscan(R), measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. ResultsNMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrodes placement, to be efficient and valid in Cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular blockade at equivalent doses to clinical doses in humans. Rocuronium-induced profound neuromuscular blockade could be reverted using the cyclodextrin sugammadexs reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. ConclusionThese results support the use of non-human primate models for neuromuscular blockade monitoring and testing novel NMBA or their reversal agents.

pathology↗

bioRxiv2023

Multimodal mucosal and systemic immune characterization of a novel non-human primate trachoma model highlights the critical role of local immunity during acute phase disease

BackgroundTrachoma -the leading cause of blindness worldwide as a result of infection-is caused by repeated Chlamydia trachomatis (Ct) conjunctival infections. Disease develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and the severity of reinfections. The immune system is a pivotal aspect of disease, involved in disease aggravation, but also key for exploitation in development of a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. Methodology/Principal FindingsThe conjunctiva of non-human primate (NHP, Cynomolgus monkeys -Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis revealed an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, before a later phase monocytic influx accompanied by a decrease in other immune cells, and tear fluid cytokines returning to initial levels. Conclusion/SignificanceOur NHP model accurately reproduces acute trachoma clinical signs, allowing for the precise assessment of the local immune responses in infected eyes. A progressing immune response occurred for weeks after exposure to Ct, which subsided into persistence of innate immune responses. Understanding these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies to prevent disease. Author SummaryChlamydia trachomatis is the leading infectious cause of blindness worldwide. The pathogenesis of trachoma is more complicated than other types of bacterial conjunctivitis: clinical signs of trachoma are rooted in repeated Chlamydia trachomatis infections of the inner eyelid surfaces, which roughens the skin. This lead to eyelid deformation and lashes rubbing on the cornea, which across multiple years of abrasion, ends with corneal opacification. The immune system is a pivotal aspect of disease, involved in disease aggravation, but also key for exploitation in development of a trachoma vaccine. Here we describe a non-human primate model of trachoma that accurately reproduces acute human eye disease, allowing for the precise assessment of the local immune responses in infected eyes. A progressing immune response occurred 4 weeks after exposure to Ct, which subsided into persistence of innate immune responses. Understanding these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies to prevent disease.

microbiology↗

bioRxiv2023

Sotrovimab retains activity against SARS-CoV-2 Omicron variant BQ.1.1 in a non-human primate model

The SARS-CoV2 Omicron variants have acquired new Spike mutations leading to escape from the most of the currently available monoclonal antibody treatments reducing the options for patients suffering from severe Covid-19. Recently, both in vitro and in vivo data have suggested that Sotrovimab could retain partial activity against recent omicron sub-lineage such as BA.5 variants, including BQ.1.1. Here we report full efficacy of Sotrovimab against BQ.1.1 viral replication as measure by RT-qPCR in a non-human primate challenge model.

pathology↗

bioRxiv2021

Immunization with synthetic SARS-CoV-2 S glycoprotein virus-like particles protects Macaques from infection

The SARS-CoV-2 pandemic causes an ongoing global health crisis, which requires efficient and safe vaccination programs. Here, we present synthetic SARS-CoV2 S glycoprotein-coated liposomes that resemble in size and surface structure virus-like particles. Soluble S glycoprotein trimers were stabilized by formaldehyde cross-linking and coated onto lipid vesicles (S-VLP). Immunization of cynomolgus macaques with S-VLPs induced high antibody titers and TH1 CD4+ biased T cell responses. Although antibody responses were initially dominated by RBD specificity, the third immunization boosted non-RBD antibody titers. Antibodies showed potent neutralization against the vaccine strain and the Alpha variant after two immunizations and robust neutralization of Beta and Gamma strains. Challenge of animals with SARS-CoV-2 protected all vaccinated animals by sterilizing immunity. Thus, the S-VLP approach is an efficient and safe vaccine candidate based on a proven classical approach for further development and clinical testing.

immunology↗