Effectiveness of the adapted bivalent mRNA COVID-19 vaccines against hospitalisation in individuals aged ≥ 60 years during the Omicron XBB lineage-predominant period: VEBIS SARI VE network, Europe, February to August, 2023

Members of the European Hospital Vaccine Effectiveness Group: Portugal: Ana Paula Rodrigues, Débora Pereira, Susana Costa Maia e Silva, Paula Pinto, Cristina Bárbara, António Pais de Lacerda, Raquel Guiomar and Camila Henriques.The European Medicines Agency (EMA) authorised four adapted bivalent mRNA COVID-19 vaccines for use against COVID-19 in September/October 2022: Comirnaty (BNT162b2; Pfizer-BioNTech) and Spikevax (mRNA-1273; Moderna) Original/Omicron BA.1 and Original/Omicron BA.4–5 [1]. During autumn 2022, all European Union/European Economic Area (EU/EEA) countries had vaccination campaigns in place to administer a booster dose, with several countries using the adapted bivalent vaccines [2]. The Omicron-descendent XBB lineage and XBB.1.5 sub-lineage became variants of interest in March 2023 [3]. We estimated the effectiveness of the COVID-19 bivalent vaccines against hospitalisation with PCR-confirmed SARS-CoV-2 infection among patients aged ≥ 60 years with severe acute respiratory infection (SARI) during the XBB lineage-predominant period.The ‘Vaccine Effectiveness, Burden and Impact Studies studies’ (VEBIS) is a project of the European Centre for Disease Prevention and Control (ECDC) run under the framework con tract No. ECDC/2021/016.info:eu-repo/semantics/publishedVersio

Multilayered and versatile functions of the HIV-2 envelope glycoprotein in the viral replication cycle

The Human Immunodeficiency Virus type 2 (HIV-2) is the second etiologic agent causing AIDS (acquired immune deficiency syndrome) in the human host. However, this retrovirus may be considered as an attenuated model of retroviral infection since the HIV-2-infected individuals show a longer asymptomatic phase, lower plasmatic viral loads without antiviral therapy, and do not experience AIDS-like symptoms in 60-70% of cases, in striking contrast with HIV-1-infected patients. HIV-2-positive individuals appear to control the virus replication and the main hypothesis that could explain this phenotype is a strong T cell-mediated immunity and a robust early innate immune response against HIV-2. In this thesis research project, we focus on a host restriction factor involved in the antiviral immune response: BST-2/Tetherin. This interferon (IFN)-inducible protein is able to retain the budding virions at the plasma membrane of the infected cells, and promotes the endocytosis and degradation of the “tethered” viral particle. HIVs have evolved means to counteract BST-2/Tetherin in order to ensure the viral dissemination in the human host. HIV-1 uses the accessory Vpu protein to bind and degrade BST-2/Tetherin, whereas HIV-2 - that lacks Vpu - relies on its envelope (Env) glycoprotein. It has been reported that the HIV-2 envelope glycoproteins bind and remove BST-2 from the cell membrane, but this countermeasure does not result in the degradation of BST-2. HIV-2 Env and BST-2 interact mainly through their ectodomain. However, little was known concerning the domain in the Env protein that can exert this function. During this research project, we first revealed the precise motif within the ectodomain of HIV-2 Env protein involved in the anti-tetherin function. Indeed, we demonstrated that the N659 residue is clearly involved in the antagonism of BST-2/Tetherin. We also showed that the cytoplasmic tail (CT) of the HIV-2 Env protein cooperates in this anti-tetherin function. BST-2/Tetherin can also prime the expression of numerous antiviral genes via the activation of the NF-κB signaling pathway - a key regulator of the innate and adaptive immune response toward viral pathogens. The activation of the NF-κB transcription factor results in the expression of numerous genes involved in the antiviral response. Interestingly, we demonstrated that the HIV-2 Env glycoprotein, like HIV-1 Env, acts as a potent activator of the NF-κB signaling pathway and that the HIV-2 Env CT is involved in this activation. However, while HIV-1 Vpu completely abolishes the activation of NF-κB at the late stages of infection mainly through the potent antagonism of BST-2, we revealed that HIV-2 is unable to inhibit NF-κB primarily due to the inefficient Env-mediated BST-2 antagonism. As a consequence, numerous antiviral genes are upregulated during the late stages of the HIV-2 viral cycle, as compared with HIV-1. Thus, we may conclude that the differential regulation of the NF-κB-mediated antiviral response - through the viral countermeasure of the BST-2 restriction - is a major determinant of the differences between HIV-1 and HIV-2 pathogenesis, and may explain at least partly the stronger immunological control of the HIV-2 infection commonly seen in the majority of HIV-2-infected individuals.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Single Amino Acid Substitution N659D in HIV-2 Envelope Glycoprotein (Env) Impairs Viral Release and Hampers BST-2 Antagonism.

BST-2 or tetherin is a host cell restriction factor that prevents the budding of enveloped viruses at the cell surface, thus impairing the viral spread. Several countermeasures to evade this antiviral factor have been positively selected in retroviruses: the human immunodeficiency virus type 2 (HIV-2) relies on the envelope glycoprotein (Env) to overcome BST-2 restriction. The Env gp36 ectodomain seems involved in this anti-tetherin activity, however residues and regions interacting with BST-2 are not clearly defined. Among 32 HIV-2 ROD Env mutants tested, we demonstrated that the asparagine residue at position 659 located in the gp36 ectodomain is mandatory to exert the anti-tetherin function. Viral release assays in cell lines expressing BST-2 showed a loss of viral release ability for the HIV-2 N659D mutant virus compared to the HIV-2 wild type virus. In bst-2 inactivated H9 cells, those differences were lost. Subtilisin treatment of infected cells demonstrated that the N659D mutant was more tethered at the cell surface. Förster resonance energy transfer (FRET) experiments confirmed a direct molecular link between Env and BST-2 and highlighted an inability of the mutant to bind BST-2. We also tested a virus presenting a truncation of 109 amino acids at the C-terminal part of Env, a cytoplasmic tail partial deletion that is spontaneously selected in vitro. Interestingly, viral release assays and FRET experiments indicated that a full Env cytoplasmic tail was essential in BST-2 antagonism. In HIV-2 infected cells, an efficient Env-mediated antagonism of BST-2 is operated through an intermolecular link involving the asparagine 659 residue as well as the C-terminal part of the cytoplasmic tail

Short Communication: An Insertion of Seven Amino Acids in the Envelope Cytoplasmic Tail of HIV-2 Selected During Disease Progression Enhances Viral Replication.

The cytoplasmic tail (CT) of the HIV-2 envelope glycoprotein (Env) includes amino acid (aa) sequences that are similar to lentiviral lytic peptides (LLP) described in other lentiviruses. Within the putative LLP-2 region, we previously observed insertions of 3 or 7 aa in sequences deduced from plasma viral RNA of symptomatic HIV-2-infected individuals. Based on these observations, we reproduced the insertions in a molecular clone to assess their impact on replicative fitness and cell death in vitro. Using a molecular clone of the HIV-2 reference strain, site-directed mutagenesis experiments allowed the generation of plasmids with the insertion LTAI or LQRALTAI in the Env protein. The clone with 7 aa insertion enhanced viral release 8 to 11 times in infected T cells and cell viability was impaired by more than 20%, compared with the wild-type HIV-2 virus. The effect of the 3 aa insertion was milder, with a nonsignificant trend to enhance viral replication and cell death compared with the wild-type virus. Interestingly, the insertions in the Env proteins did not induce a significant increase of viral infectivity, as revealed by the infectivity assay using TZM-bl cells. The insertions in the Env CT observed in vivo from disease progressors may, therefore, be involved in the higher viral load observed in these individuals. This study may open the way to the development of a prognostic marker related to the HIV-2 infection progression

First evaluation of the Next-Generation Sequencing platform for the detection of HIV-1 drug resistance mutations in Belgium.

INTRODUCTION: The WHO urges action against the threat posed by HIV drug resistance. It is well known that the sensitivity of Next-Generation Sequencing (NGS) is greater than that of Sanger Sequencing (SS). The objective of this study was to evaluate the performance of the novel NGS HIV-1 drug resistance monitoring system. MATERIALS & METHODS: NGS analyses were performed on 67 plasma samples from HIV-1 infected patients using the Sentosa SQ HIV Genotyping Assay from Vela-Dx. This kit was used on a semi-automated Ion Torrent-based platform. Sequences were compared to those obtained by SS. Samples were analysed in the same and in separate runs. Quality controls (QC) were added to control sequencing processes of protease (PRO), reverse transcriptase (RT) and integrase (INT) regions. RESULTS: Of the 41 analysed samples, 33 (80.5%) had identical drug resistance interpretation reports. Discrepant results were observed for eight samples. Five of them were only detected by NGS and had drug resistance mutations (DRMs) with an allelic frequency below the limit of detection of the SS method (between 6.3 to 20.5%). Two DRMs were only identified using the SS method. The sequences were similar in 98.2% of cases (counting variants as mismatches) and homologous in 99.9% if missed variants. Duplicated samples in a single run were similar in 95.7% (99.9%) of cases. Duplicated samples in two different runs were 98% (100%) homologous. QC results were manually assessed with a score of 340/340 for detection of DRMs in PRO and RT and 100% for INT sequencing. CONCLUSIONS: This is the first preliminary evaluation in Belgium employing the Sentosa SQ HIV Genotyping Assay. The NGS appears to be a promising tool for the detection of DRMs in HIV-1 patients and showed a higher sensitivity compared to SS. Large studies assessing the clinical relevance of low frequency DRMs are needed

Correction: First evaluation of the Next-Generation Sequencing platform for the detection of HIV-1 drug resistance mutations in Belgium.

[This corrects the article DOI: 10.1371/journal.pone.0209561.]

29ièmes Journées Franco-Belges de Pharmacochimie: Meeting Report

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report

Modulation of the NF-κB signaling pathway by the HIV-2 envelope glycoprotein and its incomplete BST-2 antagonism.

The HIVs have evolved by selecting means to hijack numerous host cellular factors. HIVs exploit the transcription factor NF-κB to ensure efficient LTR-driven gene transcription. However, NF-κB is primarily known to act as a key regulator of the proinflammatory and antiviral responses. Interestingly, retroviruses activate NF-κB during early stages of infection to initiate proviral genome expression while suppressing it at later stages to restrain expression of antiviral genes. During HIV-1 infection, diverse viral proteins such as Env, Nef and Vpr have been proposed to activate NF-κB activity, whereas Vpu has been shown to inhibit NF-κB activation. It is still unclear how HIV-2 regulates NF-κB signaling pathway during its replication cycle. Here we confirm that human BST-2 and HIV-1 Env proteins can trigger potent activation of NF-κB. Importantly, we demonstrate for the first time that the HIV-2 Env induces NF-κB activation in HEΚ293T cells. Furthermore, the anti-BST-2 activity of the HIV-2 Env is not sufficient to completely inhibit NF-κB activity

Study of Viral Load as A Predictive Marker of the Evolution of HIV Type 2 Infection in Burkina Faso

BACKGROUND: HIV - 2 infection is characterized by low sexual and vertical transmission and slow clinical and immunological progression. However, it can lead to AIDS. Viral load measurement is a predictive test of the success or failure of antiretroviral therapy. In order to evaluate the efficacy of ARV treatment, we measured plasma viral load, and CD4 T - cell counts in 68 patients, of whom 56 were HIV - 2 infected and 12 were HIV - 1/HIV - 2 co - infected. METHOD: We tested EDTA plasma samples stored at - 80 ° C, taken from patients followed in sentinel sites in the city of Ouagadougou. The sera were obtained by centrifugation, and the plasmatic viral load quantified by droplet double polymerase chain reaction (dd PCR), at a detection threshold of 10 copies/ml. Sociodemographic, clinical and therapeutic data were collected from patients charts and completed during an interview. RESULTS: Patients had a mean age of 53.8 ± 7.8 years with extremes of [38 - 72 years] and were predominantly females (57.4%), with a sex ratio of 0.80. There was a predominance of housewives and married couples with respectively 36.8% and 75.0% of patients. The majority of patients (77.9%) were Category A, that is, they were either asymptomatic or in the primary infection phase. 22.0% of patients were symptomatic, with 13.2% and 8.8% respectively belonging to categories B and C. The most observed opportunistic infections were shingles found in 7.3% of patients, oral candidiasis found in 5.9%, signs of weight loss (undernutrition) in 5.9% and genital herpes in 1.5% of patients. Four patients (4.7%) had hepatitis B. One case of tuberculosis (1.5%) was reported. The therapeutic combination of protease inhibitors (Lopinavir / ritonavir) was the most prescribed (94, 1% of patients), 58.8% of the patients had a CD4 level < 500/mm3, and 41.2% had CD4 level ≥ 500 cells/mm3. Plasma viral load was undetectable (≤ 10 copies / ml) in 70.6% of patients, 7.3% had a viral load of 10 to 50 copies / ml, and 19.1% of patients had a high viral load (≥ 101 copies / ml). Our study showed that the highest CD4 levels are observed in patients with undetectable viral load (˂ 10copies / mL). This established that the CD4 cell count and the plasma viral load value move in the opposite direction, and are two predictors of the evolution of HIV infection, and the virological and / or immunological response to HAAR