Persistent viruses, such as human immunodeficiency virus (HIV), cause major health problems worldwide and are extraordinarily difficult to clear following the establishment of persistence. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage to the host. We model states of persistent infection in our laboratory using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Persistent LCMV infections can be established by infecting mice in utero or by infecting adult mice intravenously with specific strains of the virus. When mice are persistently infected at birth or in utero with LCMV, the virus establishes systemic persistence, infecting both peripheral tissues as well as the central nervous system (CNS). Adult LCMV carrier mice are centrally tolerant to the virus at the T cell level and thus unable to eradicate the pathogen. We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 infection in humans, including infection / impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. Both of the aforementioned models of LCMV persistence enable us to study how the immune system can be manipulated or supplemented to control a persistent viral infection in the CNS and periphery. One area of active research in the laboratory is on the development and characterization of adoptive immunotherapies to treat persistent viral infections. Total body control of persistent infections can be attained both in mice and humans by adoptively transferring anti-viral immune cells (referred to as adoptive immunotherapy). Therapies have traditionally focused on administration of anti-viral T cells. However, we recently made the observation that anti-viral B cells can accelerate clearance of a persistent viral infection. We propose that particularly challenging viruses like HIV-1 require all three arms of the adaptive immune system to engage simultaneously before viral control can occur. In the LCMV clone 13 system, we have noted that eventual control of the virus in the CNS and periphery is associated with germinal center reations and a late emerging anti-viral B cell response. To improve the efficiency of viral control, we have developed and treated mice with a B cell immunotherapy consisting of LCMV-specific B cells. Administration anti-viral B cells to mice with a persistent LCMV infection elevated circulating anti-LCMV antibodies and accelerated viral control by trapping pathogen in immune complexes. These data indicate that it is possible to harness anti-viral B cells for the benefit of controlling a persistent viral infection. We predict that usage of B cells together with anti-viral T cells may improve our ability to purge difficult to treat pathogens like HIV-1. We are presently focused on optimizing our B cell immunotherapy and defining the dynamics of germinal center reactions during persistent viral infection. Within the CNS, we are also focused on the immunotherapeutic clearance of persistently infected parenchymal cell populations like microglia and neurons. Microglia have become a centerpiece in our laboratory over the past few years given their plastic nature, interesting dynamic properties, and ability to orchestrate both sterile and antiviral immune responses. Following administration of adoptive immunotherapy in mice persistently infected from birth with LCMV, we observed that antiviral T cells recruited into the CNS promote the conversion of nearly all microglia into CD11c+ antigen presenting cells (APCs). CD11c is a marker commonly used to identify dendritic cells (DCs), and we have previously shown that interactions with host DCs are required for successful viral clearance following adoptive immunotherapy. Interestingly, microglia can also acquire DC-like properties following adoptive immunotherapy. They upregulate antigen-presenting machinery and release chemoattractants that recruit antiviral T cells. In fact, we showed using TPM that therapeutic antiviral CD8+ and CD4+ T cells directly engage CD11c+ microglia during adoptive immunotherapy. Even more impressive was the fact that these interactions resulted in viral clearance from microglia without evidence of cytopathology. We obtained data showing that microglia are resistant to apoptosis and are purged of virus in a noncytopathic manner. We postulate that microglia have acquired a mechanism to dampen the cytopathic effector mechanisms of T cells in order to help preserve brain tissue during viral clearance. We are in the process of attempting to identify these regulatory pathways.
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| Manglani, Monica; McGavern, Dorian B (2018) Intravital Imaging of Neuroimmune Interactions Through a Thinned Skull. Curr Protoc Immunol 120:24.2.1-24.2.12 |
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| Russo, Matthew V; McGavern, Dorian B (2015) Immune Surveillance of the CNS following Infection and Injury. Trends Immunol 36:637-650 |
| Giardino Torchia, Maria Letizia; Munitic, Ivana; Castro, Ehydel et al. (2015) c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8(+) memory T-cell survival. Eur J Immunol 45:2672-82 |
| Wan, Chi-Keung; Andraski, Allison B; Spolski, Rosanne et al. (2015) Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc Natl Acad Sci U S A 112:9394-9 |
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