miRNA-mediated premature T cell aging in vaccine failure during viral infection

East Tennessee State University, Johnson City TN

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Abstract

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the mechanisms by which chronic infection mediates premature T cell aging through regulation of microRNAs and leading to blunted vaccine responses, with an aim to develop effective approaches to improve vaccine efficacy in virus-infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine failure in the setting of chronic hepatitis C virus (HCV) infection. The proposal is based on the fact that co-infection of HBV with HCV and/or HIV is common due to shared risk factors, and as such HBV vaccine is required to prevent super-infection and its associated increase in morbidity and mortality; however, vaccine responses in virus-infected individuals are often blunted. This phenomenon is also observed in the elderly, who frequently fail to respond to vaccinations and attempts to improve the rate of immunizations in both infected and aged populations have been unsuccessful. This is in part due to our poor understanding of the mechanisms that inhibit vaccine responses in these settings. In studying the effect of viral infection on T cell functions, we and others have recently found that chronic HCV infection leads to T cell dysfunction mediated through up-regulation of aging markers, including killer cell lectin- like receptor subfamily G member 1 (KLRG1) and dual specific phosphatase 6 (DUSP6), concomitant with a decline of microRNA-181a (miR181) levels in CD4 T cells. Remarkably, these alterations are associated with impaired CD4 T cell functions in HCV-infected individuals and are more prominent in HBV vaccine non- responders (HBV-NR) compared to age-matched HBV vaccine responders (HBV-R). With increasing age, KLRG1 is up-regulated and leads to inhibition of T cell receptor (TCR) signaling, whereas DUSP6 is increased and leads to recalibration of the TCR activation threshold; miR181 declines to permit translation of a set of genes related to T cell inhibition. However, the mechanisms underlying miR181/KLRG1/DUSP6 expression and regulation of premature T cell aging and vaccine responses during HCV infection remain unknown. In this proposal, we hypothesize that HCV-induced loss of miR181 mediates premature T cell aging by up-regulating KLRG1 and/or DUSP6 expressions, such that targeting these inhibitory pathways may rescue impaired CD4 T cell functions and subsequently boost blunted vaccine responses in virus-infected individuals. To test this hypothesis, we will carry out the following three specific aims: Aim 1 will define the epigenetic, transcriptional and translational mechanisms that control miR181 expression in T cells during HCV infection; Aim 2 will determine the role of miR181 in regulating KLRG1 and/or DUSP6 expression in T cells during HCV infection; Aim 3 will examine the consequences of miR181 loss and KLRG1/DUSP6 expression in T cell function and vaccine response in virus-infected individuals. This translational study is significant in that it provides a working model t explore mechanisms that may be fundamental to diminished vaccine responses in general, particularly in the setting of immunocompromise by HIV, hemodialysis, transplantation, and cancer.