The scope of the article is to review the different approaches that have been used for HIV vaccines. The review is based on articles retrieved by PubMed and clinical trials from 1990 up to date. The article discusses virus complexity, protective and non‐protective immune responses against the virus, and the most important approaches for HIV vaccine development.

Exosomes are a potent means for intercellular communication. However, exosomes have received intensive research focus in immunobiology only relatively recently. Because they transport proteins, lipids and genetic material between cells, they are especially suited to amplify their parental cell's message and overcome the physical constraints of cell‐to‐cell contact, that is exosome release gives cells the ability to alter distant, non‐contiguous cells. As progress is made in this field, it has become increasingly obvious that exosomes are involved in most biological processes. In the immune system, exosomes are fundamental tools used by every immune cell type to fulfil its function and promote inflammation or tolerance. In this review, we first summarize key aspects of immune cell‐specific exosomes and their functions. Then, we describe how exosomes have been shown to be indispensable orchestrators of the immune response in two immunological scenarios, namely transplant rejection or tolerance, and tumour evasion or initiation of anti‐tumour immune responses.

BACKGROUND: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone. METHODS: We induced coxsackievirus B3 (CVB3)–mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice. RESULTS: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [ P =0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [ P =0.003]; n=10–11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4 ⁺ (cluster of differentiation 4) T cells ( P =0.025), inflammatory Ly6C ⁺ CCR2 ⁺ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes ( P =0.038), neutrophils ( P =0.001) and eosinophils ( P <0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade. CONCLUSIONS: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.

Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord bloods. The average percentage of NIMA-XD amongst total DCs was 2.6% for myeloid and 4.5% for plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p= 0.0016; pDC: p=0.024). We detected CD9⁺ EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients.

Background. Individuals harbor preexisting HLA−DR/DQ−restricted responses to collagen type V (ColV) mediated by Th17 cells under Treg control, both specific to peptides that bind to inherited HLA class II antigens. Yet after transplant, the donor−DR type somehow influences graft outcome. We hypothesized that, long after a lung or heart allograft, the particular HLA−DR type of the mismatched transplant donor transforms the specificity of the “anti−self” response. This could explain why, over long term, certain donor DRs could be more immunogenic than others. Methods. We analyzed 7 HLA−DR15^neg patients who had received a lung allograft from a DR15⁺ donor. To determine the mechanism of acquired specificity in self−reactivity, we analyzed the kinetics of DR1 (host) and DR15 (donor) peptide restriction in a heart transplant model using DR−transgenic mice. Results. Beyond 1.5 years post-lung transplant, all patients tested had acquired DR15−restricted immune responses to ColV peptides. These responses were either unrestrained Th17 type (n = 4) or Th17 controlled by Treg arising early (7 y) after transplant (n = 4). Treg suppression via conventional (transforming growth factor−β [TGF−β]) and extracellular vesicle−associated (IL−35) cytokines correlated with superior outcomes. Naïve DR1 and DR15 transgenic mice had preexisting DR−restricted responses, exclusively to ColV fragments containing DR1− or DR15−binding peptides. When HLA−DR1 transgenic recipients of a HLA−DR15 heart developed ColV reactivity post-transplant, mice that acutely rejected (20–25 d) responded only to the DR1−restricted ColV peptide epitope. In animals whose grafts survived long term, we could detect acquisition of DR from the transplant donor onto the surface of recipient dendritic cells, and immune responses against a donor DR15–restricted ColV peptide. Conclusions. These results might explain how certain donor HLA−DR types redirect host immune responses to novel peptides of critical self−antigens. Unless regulated, such responses may predispose the allograft to chronic rejection.

Objectives Emerging evidence has shown a role for tumor antigen-specific regulation in cancer. Identifying individuals with pre-existing regulatory responses may be key to understand those who are more likely to respond to Programmed Death-1 (PD-1) or PD-1 Ligand 1 (PD-L1) checkpoint blockade. We hypothesized that a functional assay could identify the role of PD-1/PD-L1 interactions on tumor-specific immune cells in the peripheral blood in patients with advanced non-small-cell lung cancer (NSCLC). Methods We performed the trans vivo delayed-type hypersensitivity assay to identify the role of PD-1/PD-L1-mediated tumor-specific immune regulation in ten patients with advanced NSCLC. Results The majority of patients had PD-1-mediated anergic immune responses towards their tumor antigens. Eight out of nine of these patients did not respond to their own tumor antigens but responded in the presence of anti-PD-1 antibody (‘PD-1 anergy’ phenotype). A minority (3/9) also had ‘active’ PD-1-mediated immune suppressive regulatory responses. Our results suggest that PD-1-anergy is a common feature of NSCLC immune responses, whereas PD-1-mediated immune suppression is present only in a minority of patients. The latter was associated with poor clinical outcomes in our sample. Conclusions Overall, our results indicate that bystander suppression or the ‘anergy-only’ phenomenon may be novel biomarkers in NSCLC and suggest prediction value based on these phenotypes.