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. Over the past year, we have pursued research focused on two important areas pertaining to persistent viral infections: immunoregulatory mechanisms and adoptive immunotherapy. One of the most exciting areas of persistent viral infection research focuses on the identification and therapeutic neutralization of molecules that suppress immune function and facilitate persistence. We theorize that the regulatory network is particularly robust within the CNS because of the need to preserve non-replicative cells such as neurons. Recent studies in the LCMV clone 13 model system have shown that therapeutic blockade of regulatory pathways such as PD-1 / PD-L1 and IL-10 can improve T cell function and promote viral clearance. We recently observed that the PD-L1 pathway is heavily upregulated in the CNS during a persistent LCMV infection. However, the mechanism by which PD-L1 regulates T cell dynamics and function was unknown. Therefore, we set out to define mechanistically how this pathway functions to suppress T cell activity in the brain and secondary lymphoid tissues during persistent infection. Using two-photon microscopy (TPM), we imaged fluorescent protein tagged LCMV specific CD8 and CD4 T cells undergoing T cell exhaustion (or loss of function) during a persistent clone 13 infection. Interestingly, T cell exhaustion was associated with a dynamic lock down. Both anti-viral CD8 and CD4 T cells formed stable immunological synapses with target cells that lasted for hours. These stable interactions appeared to simultaneously impede both T cell mobility and function. To determine the importance of the PD-1 pathway on these interactions, we administered an antagonistic antibody and monitored anti-viral T cell dynamics by TPM. Following administration of anti-PD-1, anti-viral CD8 and CD4 T cells were immediately released from synaptic lock down and become highly motile. This coincided with increased effector function, immunopathology, and overt disease. These data indicate that PD-1 / PD-L1 pathway contributes to immune exhaustion by rendering anti-viral T cells immobile. We are in the process of further evaluating how this and other regulatory pathways protect the CNS from T cell mediated injury. The other area of focus 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 to 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 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 B cells in conjugation 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 dynamics of failing versus successful anti-viral B cell responses by TPM.

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Manglani, Monica; Gossa, Selamawit; McGavern, Dorian B (2018) Leukocyte Isolation from Brain, Spinal Cord, and Meninges for Flow Cytometric Analysis. Curr Protoc Immunol 121:e44
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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
Rua, Rejane; McGavern, Dorian B (2018) Advances in Meningeal Immunity. Trends Mol Med 24:542-559
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