Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein’s globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy. Neutralizing antibodies (nAbs) represent a key principle of antiviral immunity. Protective vaccines aim at inducing nAbs to prevent viral infection, and infusion of nAbs in convalescent patient serum can offer a potent antiviral therapy. Certain viruses, however, have found ways to evade nAb control. Amongst them are high-risk pathogens of the arenavirus family such as Lassa virus (LASV), which is a frequent cause of hemorrhagic fever in West Africa. Here we unveil the molecular strategy by which arenaviruses escape antibody neutralization and avoid efficient immune control. We show that their surface is decorated with sugar moieties, serving to shield the virus against the neutralizing effect of the host’s antibodies. This immune evasion strategy differs from those described for other viruses, in which sugars impair primarily the induction of antibodies or allow for viral mutational escape. The arenavirus sugar coat renders the host nAb response inefficient and as a consequence thereof, the host fails to promptly control the infection. Our results offer a compelling explanation for the long history of failures in trying to make a nAb-based vaccine against LASV or in using convalescent serum for therapy. These mechanistic insights will support vaccine development efforts against arenaviruses such as LASV.

Interferon-driven inflammation in chronic viral infection blocks generation of sustained B cell responses. See related Research Articles by Moseman et al. and Sammicheli et al. and a Focus by Laidlaw et al.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL^eff) responses. Conversely, the induction of protective tumour-specific CTL^effand their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL^effresponses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL^effinflux triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.

Persistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection, we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infections do, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin, and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID mutant mice, chronic infection selects for GC B cells with hypermutated B cell receptors (BCRs) and neutralizing antibody formation. These findings demonstrate that, unlike for CD8+ T cells, chronic viral infection drives a functional, productive, and protective GC B cell response.

Epidemiological studies associate viral infections during childhood with the risk of developing autoimmune disease during adulthood. However, the mechanistic link between these events remains elusive. We report that transient viral infection of the brain in early life, but not at a later age, precipitates brain autoimmune disease elicited by adoptive transfer of myelin-specific CD4⁺ T cells at sites of previous infection in adult mice. Early-life infection of mouse brains imprinted a chronic inflammatory signature that consisted of brain-resident memory T cells expressing the chemokine (C-C motif) ligand 5 (CCL5). Blockade of CCL5 signaling via C-C chemokine receptor type 5 prevented the formation of brain lesions in a mouse model of autoimmune disease. In mouse and human brain, CCL5⁺ T_RM were located predominantly to sites of microglial activation. This study uncovers how transient brain viral infections in a critical window in life might leave persisting chemotactic cues and create a long-lived permissive environment for autoimmunity.

T cell factor 1 (Tcf-1) expressing CD8⁺ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8⁺ T cells (CD8⁺SL) remain poorly defined. Studying CD8⁺ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8⁺SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8⁺ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8⁺SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8⁺SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8⁺SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8⁺SL-promoting pathway in the context of chronic viral infection.