Modeling memory B cell responses in a lymphoid organ-chip to evaluate mRNA vaccine boosting.

Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a lymphoid organ-chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 spike protein mimicked a vaccine boost by inducing a massive amplification of spike-specific memory B cells, plasmablast differentiation, and spike-specific antibody secretion.

Clonal succession after prolonged antiretroviral therapy rejuvenates CD8 T cell responses against HIV-1.

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8 T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART.

Neutralization of African enterovirus A71 genogroups by antibodies to canonical genogroups.

Enterovirus 71 (EV-A71) is a major public health problem, causing a range of illnesses from hand-foot-and-mouth disease to severe neurological manifestations. EV-A71 strains have been phylogenetically classified into eight genogroups (A to H), based on their capsid-coding genomic region. Genogroups B and C have caused large outbreaks worldwide and represent the two canonical circulating EV-A71 subtypes.

SARS-CoV-2 hijacks neutralizing dimeric IgA for nasal infection and injury in Syrian hamsters.

Prevention of robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) requires evaluation of IgA neutralizing antibodies. Here, we report the efficacy of receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1, B8-dIgA2 and TH335-dIgA1 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparable neutralization potency against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding.

The Spike-Stabilizing D614G Mutation Interacts with S1/S2 Cleavage Site Mutations To Promote the Infectious Potential of SARS-CoV-2 Variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained genetically stable during the first 3 months of the pandemic, before acquiring a D614G spike mutation that rapidly spread worldwide and then generating successive waves of viral variants with increasingly high transmissibility. We set out to evaluate possible epistatic interactions between the early-occurring D614G mutation and the more recently emerged cleavage site mutations present in spike of the Alpha, Delta, and Omicron variants of concern. The P681H/R mutations at the S1/S2 cleavage site increased spike processing and fusogenicity but limited its incorporation into pseudoviruses.

A close shave: How SARS-CoV-2 induces the loss of cilia.

Wang et al. report in this issue (2022. J.

Enhanced Cross-Reactive and Polyfunctional Effector-Memory T Cell Responses by ICVAX-a Human PD1-Based Bivalent HIV-1 Gag-p41 Mosaic DNA Vaccine.

Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8 T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation.

SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation.

Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized.

SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance.

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited.

Sustained viremia suppression by SHIVSF162P3CN-recalled effector-memory CD8+ T cells after PD1-based vaccination.

HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1.

BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.

SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia.

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions.

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors.

CCR5 Revisited: How Mechanisms of HIV Entry Govern AIDS Pathogenesis.

The chemokine receptor CCR5 has been the focus of intensive studies since its role as a coreceptor for HIV entry was discovered in 1996. These studies lead to the development of small molecular drugs targeting CCR5, with maraviroc becoming in 2007 the first clinically approved chemokine receptor inhibitor. More recently, the apparent HIV cure in a patient transplanted with hematopoietic stem cells devoid of functional CCR5 rekindled the interest for inactivating CCR5 through gene therapy and pharmacological approaches.

CD4 T cell-mediated HLA class II cross-restriction in HIV controllers.

Rare individuals, termed HIV controllers, spontaneously control HIV infection by mounting efficient T cell responses against the virus. Protective CD4 T cell responses from HIV controllers involve high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope.

DNA Vaccination by Electroporation Amplifies Broadly Cross-Restricted Public TCR Clonotypes Shared with HIV Controllers.

Rare patients who spontaneously control HIV replication provide a useful model to inform HIV vaccine development. HIV controllers develop particularly efficient antiviral CD4 T cell responses mediated by shared high-affinity TCRs. To determine whether the candidate DNA vaccine ADVAX could induce similar responses, we analyzed Gag-specific primary CD4 T cells from healthy volunteers who received ADVAX DNA by electroporation.

MHC Class II Tetramer Labeling of Human Primary CD4 T Cells from HIV Infected Patients.

Major Histocompatibility Complex (MHC) tetramers have been used for two decades to detect, isolate and characterize T cells specific for various pathogens and tumor antigens. In the context of Human Immunodeficiency Virus (HIV) infection, antigen-specific CD8 T cells have been extensively studied , as they can be readily detected by HIV peptide-loaded MHC class I tetramers. In contrast, the detection of HIV-specific CD4 T cells has proven more challenging, due to the intrinsically lower clonal expansion rates of CD4 T cells, and to the preferential depletion of HIV-specific CD4 T cells in the course of HIV infection.

Public T cell receptors confer high-avidity CD4 responses to HIV controllers.

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes.

TCR clonotypes: molecular determinants of T-cell efficacy against HIV.

Because of the enormous complexity and breadth of the overall HIV-specific CD8(+) T-cell response, invaluable information regarding important aspects of T-cell efficacy against HIV can be sourced from studies performed on individual clonotypes. Data gathered from ex vivo and in vitro analyses of T-cell responses and viral evolution bring us one step closer towards deciphering the correlates of protection against HIV. HIV-responsive CD8(+) T-cell populations are characterized by specific clonotypic immunodominance patterns and public TCRs.

[IRIS: a paradoxical inflammatory reaction in patients treated simultaneously for tuberculosis and HIV].

Co-infection with Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) represents a major threat to public health worldwide. The treatment of patients coinfected by Mtb and HIV is often complicated by the occurrence of an immune reconstitution inflammatory syndrome (IRIS), resulting in the unexpected resumption of tuberculosis symptoms after the initiation of antiretroviral therapy. IRIS is associated with a rapid reconstitution of CD4(+) T cell responses specific for Mtb, which is promoted by the control of HIV replication and a high concentration of available interleukin-7.

Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome.

Objective: Patients coinfected with HIV and Mycobacterium tuberculosis frequently experience a paradoxical worsening of tuberculosis (TB) symptoms early after the initiation of combination antiretroviral therapy (cART). This immune reconstitution inflammatory syndrome (TB-IRIS) can lead to significant morbidity and needs to be distinguished from TB recurrence due to ineffective treatment. We investigated whether plasma biomarkers could predict the occurrence of TB-IRIS.