Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Persistence of diverse transcriptionally competent viral reservoirs in people living with HIV-1

Malgré les améliorations significatives apportées par la thérapie antirétrovirale à la durée et à la qualité de vie des personnes vivant avec le VIH, elle ne permet pas de complètement éliminer le virus de l’organisme. La persistance du virus est due à l’existence de réservoirs viraux, des cellules infectées de manière latente par le VIH. Ces réservoirs nécessitent un traitement antirétroviral à vie, car le virus réapparait en cas d’interruption du traitement, signifiant que l’immunité des cellules T spécifiques du VIH n’est pas restaurée. Bien que cela soit théoriquement possible, seule une fraction de personne vivant avec le VIH, appelée Contrôleurs Élites, parvient à contrôler le virus en absence de traitement. Pour la majorité des individus, l’infection par le VIH entraîne une évasion virologique ainsi qu’un épuisement et une altération des réponses cellulaires spécifiques au VIH. À ce jour, les stratégies thérapeutiques visant à éliminer les réservoirs viraux ont échoué, en partie en raison de la présence de provirus principalement défectifs dans ces réservoirs. Dans cette thèse, nous avons identifié et caractérisé les provirus défectifs latents du VIH pouvant être transcrits et/ou traduits, ainsi que la relation entre ces réservoirs et les réponses immunitaires spécifique du virus. Dans un premier temps, nous avons montré que bien que défectifs et potentiellement incapable de donner lieu à la réplication virale, ces provirus peuvent être transcrits et traduits soit par réactivation à l’aide d’agents de réversion de la latence, soit de manière spontanée. Ces réservoirs donnent lieu à plusieurs populations de réservoirs, en fonction de la présence ou de l’absence certains gènes viraux. Nous avons déterminé que ces différentes populations sont régies par le profil génomique des cellules infectées. Les provirus identifiés étaient très rarement intacts, mais l’intégrité du génome était associée à la processivité de la transcription et de la traduction. Dans un second objectif, nous avons caractérisé les réponses T CD4+ et CD8+ spécifiques du VIH avant et après le début du traitement antirétroviral. Nous avons observé que les réponses T CD4+ spécifiques étaient comparables pendant l’infection chronique et après le traitement. En revanche, les réponses T CD8+ diminuaient considérablement après l’initiation de la thérapie antirétrovirale. Nous avons également constaté que la taille du réservoir traductionnellement actif pendant le traitement antirétroviral était négativement associée aux réponses T CD8+ spécifiques avant le début de la thérapie, tandis que le réservoir incapable de traduire les protéines du VIH subsistait. Ces observations mettent en évidence le rôle des cellules T CD8+ dans le contrôle de l’infection par le VIH, comme nous l’avons observé chez les Contrôleurs Élites. Nos travaux contribuent à une meilleure compréhension des réservoirs viraux du VIH, qui pourraient potentiellement être impliqués dans l’inflammation chronique et la dysfonction immunitaire associé à la pathogénèse du VIH.Despite the significant improvement brought by antiretroviral therapy in the duration and quality of life for people living with HIV, it does not completely eliminate the virus from the body. The persistence of the virus is due to the existence of viral reservoirs, which are cells latently infected with HIV. These reservoirs require lifelong antiretroviral treatment because of the viral rebound reoccurring in case of treatment interruption. This suggests that HIV-specific T cell immunity is not restored. Although theoretically possible, only a fraction of people living with HIV, known as Elite Controllers, are able to control the virus in the absence of treatment. For the majority of individuals, HIV infection leads to virologic escape, as well as exhaustion and altered cellular responses to HIV. To date, therapeutic strategies aimed at eliminating viral reservoirs have failed, partly due to the presence of predominantly defective proviruses in these reservoirs. In this thesis, we have identified and characterized latent defective proviruses of HIV that can be transcribed and/or translated. We also have characterized the relationship between these reservoirs and the specific immune responses to the virus. Firstly, we have shown that although defective and potentially replication-incompetent, these proviruses can be transcribed and translated either through reactivation using latency reversal agents or spontaneously. These reservoirs give rise to several populations of reservoirs, depending on the presence or absence of certain viral genes. We have determined that these different populations are governed by the genomic profile of infected cells. The identified proviruses were rarely intact, and genome integrity was associated with the processivity of transcription and translation. Then, we characterized the specific CD4+ and CD8+ T cell responses to HIV before and after the initiation of antiretroviral treatment. We observed that specific CD4+ T cell responses were comparable during chronic infection and after treatment. However, CD8+ T cell responses decreased significantly after the initiation of antiretroviral therapy. We also found that the size of the translationally active reservoir during antiretroviral treatment was negatively associated with the specific CD8+ T cell responses prior to treatment initiation, while the translation-incompetent cells persisted. These observations highlight the role of CD8+ T cells in the control of HIV infection, as observed in Elite Controllers. Our work contributes to a better understanding of HIV viral reservoirs, which could potentially be involved in chronic inflammation and immune dysfunction associated with HIV pathogenesis

An extended SARS-CoV-2 mRNA vaccine prime-boost interval enhances B cell immunity with limited impact on T cells

Summary: Spacing the first two doses of SARS-CoV-2 mRNA vaccines beyond 3–4 weeks raised initial concerns about vaccine efficacy. While studies have since shown that long-interval regimens induce robust antibody responses, their impact on B and T cell immunity is poorly known. Here, we compare SARS-CoV-2 naive donors B and T cell responses to two mRNA vaccine doses administered 3–4 versus 16 weeks apart. After boost, the longer interval results in a higher magnitude and a more mature phenotype of RBD-specific B cells. While the two geographically distinct cohorts present quantitative and qualitative differences in T cell responses at baseline and after priming, the second dose led to convergent features with overall similar magnitude, phenotype, and function of CD4+ and CD8+ T cell responses at post-boost memory time points. Therefore, compared to standard regimens, a 16-week interval has a favorable impact on the B cell compartment but minimally affects T cell immunity

Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity

Abstract Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the “Interferon paradox” previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity