【medical-news】ARHR：阿德福韦酯可增强HBV和HIV/HBV合并感染者的HBV特异性细胞免疫

Augmentation of Hepatitis B Virus-Specific Cellular Immunity with Programmed Death Receptor-1/Programmed Death Receptor-L1 Blockade in Hepatitis B Virus and HIV/Hepatitis B Virus Coinfected Patients Treated with Adefovir
Abstract

The immunological parameters leading to viral persistence in chronic hepatitis B (CHB) are not clearly established.We analyzed HBV-specific immunoregulatory mechanisms in HIV-infected and HIV-uninfected HBeAg+ CHB patients to determine (1) the roles of immunoregulatory pathways, (2) the effect of anti-HBV therapy on immunoregulatory pathways, and (3) the role of immunomodulatory therapy to overcome the effect of T regulatory cells (Tregs, CD4+CD25+FoxP3+) in HBV-infected individuals. A prospective, double blind, randomized, placebo-controlled trial treated HBV (HIV+/–)-infected patients with adefovir 10 mg daily or placebo for 48 weeks.HBV viral load (VL), immunophenotying, and functional studies were performed at multiple time points. Suppression of HBV VL with adefovir leads to decreased peripheral expansion of Tregs. While declining, Tregs significantly inhibit cytokine-secreting HBV-specific CD8+ T cell responses over 48 weeks of anti-HBV adefovir therapy (p<0.05). A large proportion of these Tregs express programmed death receptor-1 (PD-1), blockade of Which in vitro leads to improved cytokine-secreting HBV-specific CD8+ T cell responses, particularly in HIV/HBV-coinfected patients (p<0.05). Peripheral expansion of Treg levels correlated with HBV viral load and decreased HBV-specific CD8+ T cells. PD-1 blockade increased survival of HBV-specific CD8+ T cells, removing the inhibitory effect of PD-1+ peripheral Tregs. Hence therapies involving PD-1 blockade in combination with directly acting antivirals should be investigated to reduce the need for life-long directly acting antiviral therapy.
Introduction
Globally, about350millionpeople live with chronic hepatitis B (CHB), a leading cause of hepatocellular carcinoma and cirrhosis.Due to shared routes of transmission, an estimated two to four million CHB patients are coinfected with HIV-1.While use of highly active antiretroviral therapy has slowed HIV progression, prolonged survival has increased the risk of liver-related mortality in persons coinfected with HIV-1 and hepatitis B virus (HBV).Furthermore, individuals with HIV-1 exposed to HBV have a greater risk of developing chronicity, a lower rate of spontaneous HBsAg and HBeAg seroconversion, a higher level of HBV DNA, and modest responses to antiviral treatment compared with HIV-uninfected individuals.Although directly acting nucleoside analogs have been shown to suppress HBV replication in vivo to below the level of detection only interferon-a(IFN)-based therapy has been shown to eradicate HBV by boosting host immunity against HBV.The differential treatment responses observed between immunomodulatory (IFN) and nucleoside analog HBV drugs suggest that an immune-mediated mechanism directed toward HBV is essential for clearance of HBV and development of protective immunity. However, IFN is associated with significant adverse events and poor tolerance.Enhancement of HBV specific immunity using novel immunomodulatory agents offers a promising strategy for eradication of HBV in CHB patients.
Most studies have shown that the peripheral HBV specific immune response is weak in CHB patients.Recent studies, however, have shown a higher percentage of T regulatory cells (Treg) in the peripheral blood of CHB patients as compared to uninfected individuals and a positive correlation between Treg activity and HBV viral load among HBeAg-negative CHB patients.Tregs, demarcated by CD4+CD24+FoxP3+ expression,inhibit effective virus-specific immune responses and can also express programmed death receptor-1 (PD-1), which further deters immune responses when expressed on CD4+, CD8+,NK T cells, monocytes, or B cells.In this study, we investigated the immunoregulatory mechanisms that suppress HBV-specific immunity in HIV-positive and HIV negative CHB patients and explored methods to augment the HBV-specific immune response thereby enhancing the potential for HBV eradication.
Discussion
Our study demonstrates that in both HBV and HIV/HBV CHB patients, expansion of HBV-specific peripheral Treg cells correlates with peripheral HBV DNA levels. Control of HBV replication with adefovir was associated with decreased Treg numbers and function. Furthermore, we demonstrated enhanced HBV-specific effector cytotoxic T cells after addition of PD-1 blockade in vitro in HIV/HBV-coinfected patients. Further studies are needed to determine whether the expansion of peripheral Tregs is a direct result of ongoing uncontrolled HBV replication or a bystander effect of the immunological events associated with CHB.
In conclusion, we demonstrate that patients with chronic hepatitis B (HIV+/–) possess high Treg levels, which inhibit anti-HBV immunity. Control of HBV viremia is associated with decreased Treg levels and a boost in HBV-specific immunity.However, eradication of HBV in CHB patients requires a significant increase in HBV-specific effector response, which will likely require an immune-based therapy. PD-1 blockade boosts the HBV-specific CD8+ T cell effector response, particularly in HIV/HBV-coinfected patients, and alone or in combination with other immune-based therapies may result in preferential expansion of long-lived effector memory cells and reduce the need for life long DAT in CHB patients.