Neutralizing monoclonal antibodies to human immunodeficiency virus type 1 do not inhibit viral transcytosis through mucosal epithelial cells

AbstractHIV-1 transcytosis has been proposed as a potential mechanism allowing the virus to cross the epithelium during mucosal transmission. Epitopes of the HIV-1 envelope involved in this process have not been identified yet. Here, we assessed a large panel of HIV neutralizing antibodies recognizing well-characterized epitopes of the HIV-1 envelope for their ability to block HIV-1 transcytosis across a confluent epithelial monolayer.We found that all of the 13 HIV-1-specific monoclonal antibodies tested in the present study, including the three broadly neutralizing antibodies 2F5, 2G12 and IgG1b12, lacked the ability to inhibit transcytosis of cell-free and cell-associated R5- as X4-tropic HIV-1 across a tight and polarized monolayer of HEC-1 epithelial cells. In contrast, anti-gp160 polyclonal antibodies purified from serum or breast milk of HIV-1-infected individuals potently inhibited HIV-1 transcytosis. Furthermore, polymeric S-IgA exhibited similar ability to inhibit transcytosis compared to IgG despite their lower anti-gp160 specific activity. Together, these results demonstrate that the major neutralizing envelope epitopes of HIV-1 are not involved in HIV-1 transcytosis, and suggest that surface agglutination of virus particles may participate to the blocking effect observed with both polyclonal and polymeric anti-gp160 immunoglobulins

Differential in vitro inhibitory activity against HIV-1 of alpha-(1-3)- and alpha-(1-6)-D-mannose specific plant lectins : Implication for microbicide development

<p>Abstract</p> <p>Background</p> <p>Plant lectins such as <it>Galanthus nivalis </it>agglutinin (GNA) and <it>Hippeastrum hybrid </it>agglutinin (HHA) are natural proteins able to link mannose residues, and therefore inhibit HIV-target cell interactions. Plant lectins are candidate for microbicide development.</p> <p>Objective</p> <p>To evaluate the activity against HIV of the mannose-specific plant lectins HHA and GNA at the cellular membrane level of epithelial cells and monocyte-derived dendritic cells (MDDC), two potential target cells of HIV at the genital mucosal level.</p> <p>Methods</p> <p>The inhibitory effects of HHA and GNA were evaluated on HIV adsorption to genital epithelial HEC-1A cell line, on HIV transcytosis throughout a monolayer of polarized epithelial HEC-1A cells, on HIV adsorption to MDDC and on transfer of HIV from MDDC to autologous T lymphocytes.</p> <p>Results</p> <p>HHA faintly inhibited attachment to HEC-1A cells of the R5-tropic HIV-1_Ba-Lstrain, in a dose-dependent manner, whereas GNA moderately inhibited HIV adsorption in the same context, but only at high drug doses. Only HHA, but not GNA, inhibited HIV-1_JR-CSFtranscytosis in a dose-dependent manner. By confocal microscopy, HHA, but not GNA, was adsorbed at the epithelial cell surface, suggesting that HHA interacts specifically with receptors mediating HIV-1 transcytosis. Both plant lectins partially inhibited HIV attachment to MDDC. HHA inhibited more efficiently the transfer of HIV from MDDC to T cell, than GNA. Both HHA and GNA lacked toxicity below 200 μg/ml irrespective the cellular system used and do not disturb the monolayer integrity of epithelial cells.</p> <p>Conclusion</p> <p>These observations demonstrate higher inhibitory activities of the lectin plant HHA by comparison to GNA, on HIV adsorption to HEC-1A cell line, HIV transcytosis through HEC-1A cell line monolayer, HIV adsorption to MDDC and HIV transfer from MDDC to T cells, highlighting the potential interest of HHA as effective microbicide against HIV.</p

Longitudinal evaluation of the impact of immunosuppressive regimen on immune responses to COVID-19 vaccination in kidney transplant recipients.

International audienceImmunocompromised patients have a high risk of death from SARS-CoV-2 infection. Vaccination with an mRNA vaccine may protect these patients against severe COVID-19. Several studies have evaluated the impact of immune-suppressive drug regimens on cellular and humoral responses to SARS-CoV-2 variants of concern in this context. We performed a prospective longitudinal study assessing specific humoral (binding and neutralizing antibodies against spike (S) and T-lymphocyte (cytokine secretion and polyfunctionality) immune responses to anti-COVID-19 vaccination with at least two doses of BNT162b2 mRNA vaccine in stable kidney transplant recipients (KTR) on calcineurin inhibitor (CNI)- or belatacept-based treatment regimens. Fifty-two KTR−31 receiving CNI and 21 receiving belatacept—were enrolled in this study. After two doses of vaccine, 46.9% of patients developed anti-S IgG. Anti-spike IgG antibodies were produced in only 21.4% of the patients in the belatacept group, vs. 83.3% of those in the CNI group. The Beta and Delta variants and, more importantly, the Omicron variant, were less well neutralized than the Wuhan strain. T-cell functions were also much weaker in the belatacept group than in the CNI group. Renal transplant patients have an impaired humoral response to BNT162b2 vaccination. Belatacept-based regimens severely weaken both humoral and cellular vaccine responses. Clinically, careful evaluations of at least binding IgG responses, and prophylactic or post-exposure strategies are strongly recommended for transplant recipients on belatacept-based regimens

J Infect Dis

BACKGROUND: The EBL2001 phase 2 trial tested the two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine in Europe. Safety and humoral immunogenicity assessments led to EU market authorization in 2020. Complementary analyses of immune responses are warranted to better characterize vaccine effects. METHODS: We conducted an ancillary study to analyze changes in the serum and cellular responses. Serum biomarkers of activation/inflammation were evaluated using a Luminex assay. Vaccine-elicited T cell responses and functions were evaluated assessing their phenotype, cytokine production, proliferation and cytotoxic potential. Integrated data analysis was performed through correlation and principal component analysis of serum biomarkers and cellular immune responses. RESULTS: Forty-eight volunteers were included. The Ad26.ZEBOV, MVA-BN-Filo vaccine elicited: i) serum increase of inflammatory/activation markers mainly at 1 day after the Ad26.ZEBOV vaccine; ii) durable EBOV-specific T cell proliferation and CD8+ T cells exhibiting a cytotoxic phenotype after Ad26.ZEBOV prime, after MVA-BN-Filo boost and 6 months post vaccination. Integrated analysis revealed correlations between: i) EBOV-specific CD8+ T cell proliferation and cytotoxic phenotype; ii) high EBOV-specific CD8+ T cell cytotoxic phenotype and low inflammatory marker IL-8 at day 1 post vaccination. DISCUSSION: This study provides unique insights into the in vivo contribution of proliferation/cytotoxic CD8+ T cells and inflammation to the Ad26.ZEBOV, MVA-BN-Filo vaccine-induced potency.Initiative for the creation of a Vaccine Research Institut

Neutrophil Activation and Immune Thrombosis Profiles Persist in Convalescent COVID-19

International audiencePurpose Following a severe COVID-19 infection, a proportion of individuals develop prolonged symptoms. We investigated the immunological dysfunction that underlies the persistence of symptoms months after the resolution of acute COVID-19. Methods We analyzed cytokines, cell phenotypes, SARS-CoV-2 spike-specific and neutralizing antibodies, and whole blood gene expression profiles in convalescent severe COVID-19 patients 1, 3, and 6 months following hospital discharge. Results We observed persistent abnormalities until month 6 marked by (i) high serum levels of monocyte/macrophage and endothelial activation markers, chemotaxis, and hematopoietic cytokines; (ii) a high frequency of central memory CD4 + and effector CD8 + T cells; (iii) a decrease in anti-SARS-CoV-2 spike and neutralizing antibodies; and (iv) an upregulation of genes related to platelet, neutrophil activation, erythrocytes, myeloid cell differentiation, and RUNX1 signaling. We identified a “core gene signature” associated with a history of thrombotic events, with upregulation of a set of genes involved in neutrophil activation, platelet, hematopoiesis, and blood coagulation. Conclusion The lack of restoration of gene expression to a normal profile after up to 6 months of follow-up, even in asymptomatic patients who experienced severe COVID-19, signals the need to carefully extend their clinical follow-up and propose preventive measures