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.
As is observed in the elderly, individuals with HCV or HIV infection often do not respond well to HBV vaccinations, and overall efforts to boost vaccine responses in virally infected hosts have been unsuccessful-- in part due to our poor understanding of the underlying mechanisms. Based on our preliminary studies, we propose that HCV may cause premature T cell aging by up-regulating senescent markers such as KLRG1/DUSP6 through inhibiting miR181, dampening appropriate T cell responses to vaccinations during chronic infection. This project aims to explore how the expressions of these negative signaling molecules are regulated and interplay in CD4 T cells; and whether controlling these inhibitory pathways affects immune (vaccine) responses in HCV-infected patients. Understanding this mechanism is important for developing effective approaches to improve vaccine responses in chronically infected individuals. This study is thus fundamentally important, clinically significant, timely, and highly relevant to public health.
|Wang, Ling; Zhao, Juan; Ren, Junping et al. (2016) Protein phosphatase 1 abrogates IRF7-mediated type I IFN response in antiviral immunity. Eur J Immunol 46:2409-2419|
|Ren, J P; Ying, R S; Cheng, Y Q et al. (2016) HCV-induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T-cell development. J Viral Hepat 23:755-66|
|Ren, Jun P; Zhao, Juan; Dai, Jun et al. (2016) Hepatitis C virus-induced myeloid-derived suppressor cells regulate T-cell differentiation and function via the signal transducer and activator of transcription 3 pathway. Immunology 148:377-86|
|Zhou, Yun; Li, Guang Y; Ren, Jun P et al. (2016) Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via Î”Np63-miR-181a-Sirt1 pathway. J Leukoc Biol 100:1201-1211|
|Wang, Ling; Zhao, Juan; Ren, Jun P et al. (2016) Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AIDS 30:1521-31|
|Dai, Jun; El Gazzar, Mohamed; Li, Guang Y et al. (2015) Myeloid-derived suppressor cells: paradoxical roles in infection and immunity. J Innate Immun 7:116-26|
|Li, Guang Y; Zhou, Yun; Ying, Ruo S et al. (2015) Hepatitis C virus-induced reduction in miR-181a impairs CD4(+) T-cell responses through overexpression of DUSP6. Hepatology 61:1163-73|
|Wang, Ling; Li, Guangyu; Yao, Zhi Q et al. (2015) MicroRNA regulation of viral immunity, latency, and carcinogenesis of selected tumor viruses and HIV. Rev Med Virol 25:320-41|
|Cheng, Yong Q; Ren, Jun P; Zhao, Juan et al. (2015) MicroRNA-155 regulates interferon-Î³ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection. Immunology 145:485-97|