Phenotypic properties of envelope glycoproteins of transmitted HIV-1 variants from patients belonging to transmission chains.

OBJECTIVE: Transmission of HIV-1 involves a bottleneck in which generally a single HIV-1 variant from a diverse viral population in the transmitting partner establishes infection in the new host. It is still unclear to what extent this event is driven by specific properties of the transmitted viruses or the result of a stochastic process. Our study aimed to better characterize this phenomenon and define properties shared by transmitted viruses. DESIGN: We compared antigenic and functional properties of envelope glycoproteins of viral variants found during primary infection in 27 patients belonging to eight transmission chains. METHODS: We generated pseudotyped viruses expressing Env variants of the viral quasispecies infecting each patient and compared their sensitivity to neutralization by eight human monoclonal broadly neutralizing antibodies (HuMoNAbs). We also compared their infectious properties by measuring their infectivity and sensitivity to various entry inhibitors. RESULTS: Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity, providing evidence that the transmission bottleneck is mainly nonstochastic. Transmitted viruses were CCR5-tropic, sensitive to MVC, and resistant to soluble forms of CD4, irrespective of the cluster to which they belonged. They were also sensitive to HuMoNAbs that target V3, the CD4-binding site, and the MPER region, suggesting that the loss of these epitopes may compromise their capacity to be transmitted. CONCLUSION: Our data suggest that the transmission bottleneck is governed by selective forces. How these forces confer an advantage to the transmitted virus has yet to be determined

Control of embryonic stem cells self-renewal and differentiation via coordinated splicing and translation of YY2

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Functional properties of envelope glycoproteins of transmitted HIV-1 variants and their evolution during the infection or over the course of the epidemic

Lors de la transmission sexuelle du VIH-1, un seul ou un nombre très limité de variants viraux sont transmis parmi ceux présents chez le donneur. Il est important de comprendre si le variant transmis est sélectionné aléatoirement parmi ceux présents chez le donneur ou s’il possède un avantage sélectif qui le prédispose à établir plus efficacement une nouvelle infection. Lors de nos différents travaux, nous avons pu observer chez quatre patients une évolution parallèle des propriétés génétiques, antigéniques et fonctionnelles de la glycoprotéine d’enveloppe au cours de l’infection. L’évolution de certaines propriétés est répercutée à l’échelle populationnelle. Néanmoins nous avons montré que malgré ces évolutions, les virus transmis au sein d’une même chaîne de transmission présentent des propriétés biologiques conservées. L’ensemble de nos résultats vont en faveur d’une sélection d’un variant viral avec des propriétés particulières lors de la transmission. De plus le variant transmis possède une région V3 particulièrement conservée associée à un tropisme CCR5, une sensibilité au Maraviroc et semble avoir besoin d’un taux élevé de CD4 à la surface de la cellule cible.During HIV-1 sexual transmission, a single virus among the numerous viral variants present in the donor is transmitted most often. The key question is to understand if transmitted variants are randomly selected among variants from the donor or they have biological properties that predispose them to establish more efficiently a new infection. We observed a parallel evolution of genetic, antigenic and functional properties of the envelope glycoprotein in four patients during the infection. In addition, the evolution of some properties is also observed at the populational level. However, we showed that transmitted variants from a same transmission chain share similar biological properties. Together our results suggest that the transmission bottleneck is mainly non-stochastic and involves the selection viral variants harboring specific phenotypic properties. Despite transmitted variants have a conserved V3 region associated with a CCR5 tropism, sensitivity to Maraviroc and seem to require high level of CD4 to efficiently infect target cells

Ingénierie de lymphocytes B humains produisant des anticorps neutralisant le virus VIH-1 par édition génique CRISPR-Cas9

Les anticorps (ou immunoglobulines, Ig) produits par les lymphocytes B sont essentiels aux réponses immunitaires induites par les infections et les vaccins. Les anticorps sont des glycoprotéines hétérodimériques résultant de l’association de deux chaînes lourdes (IgH), et de deux chaînes légères (IgL) d’immunoglobuline. Les chaînes IgH et IgL possèdent des régions « hypervariables », également appelées en anglais complementarity determining regions (CDR), situées dans leurs domaines variables, VH et VL, qui, en se combinant, forment le site de liaison à l’antigène ou paratope

SARS-CoV-2 infection in domestic rats after transmission from their infected owner

We report the transmission of SARS-CoV-2 Omicron variant from a COVID-19 symptomatic individual to two domestic rats, one of which developed severe symptoms. Omicron carries several mutations which permit rodent infection. This report demonstrates that pet, and likely wild, rodents could therefore contribute to SARS-CoV-2 spread and evolution

Drift of the Envelope Glycoprotein of HIV-1 Clade B towards Higher Infectious Properties over the Course of the Epidemic

International audienc

Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic

International audienceWe showed previously that during the HIV/AIDS epidemic, the envelope glycoprotein (Env) of HIV-1, and in particular, the gp120 subunit, evolved toward an increased resistance to neutralizing antibodies at a population level. Here, we considered whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. We tested the infectivity of a panel of Env-pseudotyped viruses derived from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010). Pseudotyped viruses harboring Env from patients infected during the most recent period were approximately 10-fold more infectious in cell culture than those from patients infected at the beginning of the epidemic. This was associated with faster viral entry kinetics: contemporary viruses entered target cells approximately twice as fast as historical viruses. Contemporary viruses were also twice as resistant as historical viruses to the fusion inhibitor enfuvirtide. Resistance to enfuvirtide correlated with a resistance to CCR5 antagonists, suggesting that contemporary viruses expanded their CCR5 usage efficiency. Viruses were equally captured by DC-SIGN, but after binding to DC-SIGN, contemporary viruses infected target cells more efficiently than historical viruses. Thus, we report evidence that the infectious properties of the envelope glycoprotein of HIV-1 increased during the course of the epidemic. It is plausible that these changes affected viral fitness during the transmission process and might have contributed to an increasing virulence of HIV-1.IMPORTANCE Following primary infection by HIV-1, neutralizing antibodies (NAbs) exert selective pressure on the HIV-1 envelope glycoprotein (Env), driving the evolution of the viral population. Previous studies suggested that, as a consequence, Env has evolved at the HIV species level since the start of the epidemic so as to display greater resistance to NAbs. Here, we investigated whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. Our data provide evidence that the infectious properties of the HIV-1 Env increased during the course of the epidemic. These changes may have contributed to increasing virulence of HIV-1 and an optimization of transmission between individual

Variants with the N501Y mutation extend SARS-CoV-2 host range to mice, with contact transmission

Receptor recognition is a major determinant of viral host range, infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with novel hosts, and the high mutation rate of RNA viruses may explain their frequent host shifts. SARS-CoV-2 extensive circulation in humans results in the emergence of variants, including variants of concern (VOCs) with diverse mutations notably in the spike, and increased transmissibility or immune escape. Here we show that, unlike the initial and Delta variants, the three VOCs bearing the N501Y mutation can infect common laboratory mice. Contact transmission occurred from infected to naive mice through two passages. This host range expansion likely results from an increased binding of the spike to the mouse ACE2. Together with the observed contact transmission, it raises the possibility of wild rodent secondary reservoirs enabling the emergence of new variants

Distinct systemic and mucosal immune responses to SARS-CoV-2

Posté le 2 mars 2021 sur MedRxivCoordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes