Although it is widely accepted that type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin-producing β-cells in the pancreas, little is known about the events leading to islet autoimmunity. Epidemiological and genetic data have associated virus infections and antiviral type I interferon (IFN-I) response genes with T1D. Genetic variants in the T1D risk locus interferon induced with helicase C domain 1 (IFIH1) have been identified by genome-wide association studies to confer resistance to T1D and result in the reduction in expression of the intracellular RNA virus sensor known as melanoma differentiation–associated protein 5 (MDA5). Here, we translate the reduction in IFIH1 gene expression that results in protection from T1D. Our functional studies demonstrate that mice heterozygous at the Ifih1 gene express less than half the level of MDA5 protein, which leads to a unique antiviral IFN-I signature and adaptive response after virus infection that protects from T1D. IFIH1 heterozygous mice have a regulatory rather than effector T-cell response at the site of autoimmunity, supporting IFIH1 expression as an essential regulator of the diabetogenic T-cell response and providing a potential mechanism for patients carrying IFIH1 protective polymorphisms.

Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate (‘Kick’) the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host’s immune system itself will eliminate (‘Kill’) the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on ‘kill’ strategies in HIV cure research, and how these might work in combination with current or future kick strategies. We conducted a landscape review of HIV ‘cure’ clinical trials using ‘kick and kill’ approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a ‘kill’ agent. We extracted potential reasons why the ‘kill’ is missing from current ‘kick and kill’ strategies. We subsequently summarized and reviewed current ‘kill’ strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise. The identified ‘kick’ trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical ‘cure’ measures. Of the ‘kill’ agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional ‘kick’ with a vaccine immune booster (‘kill’). While an understanding of the efficacy of each individual component is crucial, no single ‘kick’ or ‘kill’ agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple ‘kick and kill’ interventions.

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that leads to progressive disability. The causes of the disease are still unknown. Viral infections has been linked to MS development and Epstein-Barr virus has been shown to have a strong link to MS. Here, we use an animal model of MS, experimental autoimmune encephalitis (EAE), to study how EBV can trigger MS. Since EBV does not infect rodents, we infected mice with murine gamma herpesvirus 68 (γHV-68), the murine equivalent of EBV. We found that mice previously infected with γHV-68 developed more severe EAE when compared to uninfected EAE mice and showed pathological features that recapitulate human MS. γHV-68 EAE presented with increased CD4 and CD8 T cells infiltrations in the brain, increased brain inflammation and demyelination. This model provides new insight on how EBV might be triggering MS, shedding light on the development of the disease.

Age-associated B cells (ABCs) are a recently identified, unique B cell population that displays both protective and pathogenic characteristics, depending on the context. A major role of ABCs is to protect from viral infection. ABCs expand during an array of viral infections and display various functional capacities, including secretion of antibodies and activation of T cells. Following resolution of infection, ABCs appear to persist and play a crucial role in memory and recall responses. Here, we review the currently understanding of ABCs in the antiviral response in both humans and mice. We discuss avenues for future research, including the impact of sex on the ABC population and heterogeneity of ABCs between contexts.

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS) by multiple groups working worldwide. Previously, we reported that when experimental autoimmune encephalomyelitis (EAE) was induced in mice latently infected with murine γ-herpesvirus 68 (γHV-68), the murine homolog to EBV, a disease more reminiscent of MS developed. Specifically, MS-like lesions developed in the brain that included equal numbers of IFN-γ producing CD4⁺ and CD8⁺ T cells and demyelination, none of which is observed in MOG induced EAE. Herein, we demonstrate that this enhanced disease was dependent on the γHV-68 latent life cycle and was associated with STAT1 and CD40 upregulation on uninfected dendritic cells. Importantly, we also show that, during viral latency, the frequency of regulatory T cells is reduced via a CD40 dependent mechanism and this contributes towards a strong T helper 1 response that resolves in severe EAE disease pathology. Latent γ-herpesvirus infection established a long-lasting impact that enhances subsequent adaptive autoimmune responses.