Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes

Suri, Deepak; Schilling, R; Lopes, Agnel R.; Mullerova, Ivana; Colucci, Giuseppe; Williams, Roger; Naoumov, Nikolai V.

doi:10.1016/s0168-8278(01)00215-x

Cited by 46 publications

(23 citation statements)

References 25 publications

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“…We previously showed that IFN-g produced upon stimulation of CD4 + T cells with recombinant HBcAg could inhibit HBV transcription and replication without target cell lysis (35). In the current study, high levels of these cytokines were produced by the CD8 + T cell line or the T cell clone after Agspecific stimulation in the two coculture systems.…”

Section: Discussionmentioning

confidence: 50%

CD8+ T Cell Control of Hepatitis B Virus Replication: Direct Comparison between Cytolytic and Noncytolytic Functions

Phillips

Chokshi

Riva

et al. 2009

The Journal of Immunology

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192

157

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Resolution of hepatitis B virus (HBV) infection was believed to be attributed to the cytotoxic T cell–mediated killing of infected hepatocytes. However, studies in HBV transgenic mice and HBV-infected chimpanzees revealed that T cell control of HBV replication also involves cytokine-mediated noncytolytic mechanisms. The relative role of cytolytic and noncytolytic functions of virus-specific CD8+ T cells during interaction with HBV-producing hepatocytes is not well understood. By using HLA-A2 matched effector cells (CD8+ T cell line or clone) and target cells supporting full HBV replication, we demonstrate that virus-specific CD8+ T cells can inhibit HBV replication in HBV-producing hepatocytes with minimal cell lysis. Although CD8+ T cells kill a fraction of infected cells, this effect is minimal, and most of the viral inhibition is mediated by noncytolytic mechanisms. CD8+ T cells produce an array of cytokines, among which IFN-γ and TNF-α are responsible for HBV inactivation in the target cells. Blockade of IFN-γ and TNF-α abrogated the noncytolytic inhibition of HBV, indicating that these two cytokines mediate the control of HBV by noncytolytic mechanisms. Furthermore, treatment of the HBV-producing hepatocytes with rIFN-γ and rTNF-α resulted in an efficient suppression of viral replication without cytotoxicity. In contrast, coculture of the same target cells with activated HLA-mismatched mitogen-activated lymphomononuclear cells caused a marked cytolytic effect and was less effective in HBV control. These results provide direct evidence that virus-specific CD8+ T cells efficiently control HBV replication by noncytolytic mechanisms, and this effect is mediated by IFN-γ and TNF-α.

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Section: Discussionmentioning

confidence: 50%

CD8+ T Cell Control of Hepatitis B Virus Replication: Direct Comparison between Cytolytic and Noncytolytic Functions

Phillips

Chokshi

Riva

et al. 2009

The Journal of Immunology

Self Cite

192

157

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“…Cell culture systems for HBV have been developed and have been used to show that lymphocytes from patients with chronic HBV infection can inhibit viral replication in human hepatocytes by releasing IFN-␥ (42). However, the inhibition of viral replication was not complete (42), and thus factors other than IFN-␥ may be mediating the effects we have postulated. Nonetheless, similar technology could be exploited to test our hypothesis.…”

Section: Discussionmentioning

confidence: 80%

The role of cells refractory to productive infection in acute hepatitis B viral dynamics

Ciupe

Ribeiro

Dusheiko

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

177

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During acute hepatitis B virus (HBV) infection viral loads reach high levels (Ϸ10 10 HBV DNA per ml), and nearly every hepatocyte becomes infected. Nonetheless, Ϸ85-95% of infected adults clear the infection. Although the immune response has been implicated in mediating clearance, the precise mechanisms remain to be elucidated. As infection clears, infected cells are replaced by uninfected ones. During much of this process the virus remains plentiful but nonetheless does not rekindle infection. Here, we analyze data from a set of individuals identified during acute HBV infection and develop mathematical models to test the role of immune responses in various stages of early HBV infection. Fitting the models to data we are able to separate the kinetics of the noncytolytic and the cytolytic immune responses, thus explaining the relative contribution of these two processes. We further show that we need to hypothesize that newly generated uninfected cells are refractory to productive infection. Without this assumption, viral resurgence is observed as uninfected cells are regenerated. Such protection, possibly mediated by cytokines, may also be important in resolving other acute viral infections.immune response ͉ mathematical modeling ͉ viral kinetics H epatitis B virus (HBV) is a small (Ϸ3.2 kb) partially dsDNA virus that infects hepatocytes (1). There are Ͼ350 million chronic HBV carriers worldwide, and infection with HBV is the cause of significant morbidity and mortality in countries of high prevalence (2). During acute infection, HBV viral loads can reach high levels, up to 10 10 HBV DNA copies per ml of plasma, which last for several weeks, coincident with HBV infection of a large percentage of hepatocytes (3-6). Subsequently, viral loads decrease, and in 85-95% of acutely infected adults the infection is cleared (7). Patients that clear the virus tend to have stronger and more diversified CD4 ϩ and CD8 ϩ T cell responses (8, 9). In addition, clearance of the virus in acutely infected patients is usually accompanied by an alanine aminotransferase (ALT) flare. Elevated levels of ALT are indicative of liver damage and an active cell-mediated immune response. Although the immune response plays a crucial role in decreasing the viral load, the precise mechanisms are not fully understood (10).Studying the immune response to HBV during acute infection of humans is difficult, and the field has progressed by the study of experimental infection in chimpanzees, woodchucks, and ducks and transgenic mice that express HBV genes. These studies demonstrated the importance of the immune response, because acute infection in chimpanzees depleted of CD8 ϩ T cells results in delayed HBV clearance and recovery (11). However, chimpanzee studies have also shown that the initial reduction in HBV viral load occurs much earlier than any detectable cytolytic immune response, liver T cell infiltration, or liver damage (3), suggesting that some form of noncytolytic response is involved. The importance of a noncytolytic response has been conf...

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“…24 The current study extends the in vitro data that rhIL-12 can stimulate PBMC from chronic hepatitis B patients to produce IFN-␥ and increases their reactivity to HBV antigens. 16,17,25 The study design included a lead period with lamivudine treatment, based on our earlier in vitro data that the antiviral effect of IFN-␥ was more pronounced in human hepatocytes with low numbers of HBV DNA copies/cell, whereas it had minimal effect in cases with a high viral load. 16 This rationale is supported by a recent, longitudinal analysis of HBV-specific CD8ϩT-cells in chronic HBV patients, which found an inverse relationship with viremia, and these cells were present/detectable in circulation only in patients with HBV DNA Ͻ10 7 copies/mL.…”

Section: Discussionmentioning

confidence: 99%

“…15 In addition, IL-12 restored in vitro the hypo-responsiveness to viral antigens of T-cells obtained from patients with chronic hepatitis B. 16,17 We conducted a pilot study to investigate in patients with chronic hepatitis B whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater antiviral effect and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. In addition, by monitoring longitudinally the HBV-specific T-cell reactivity, the study aimed to determine whether IL-12-stimulated Tcell responsiveness to HBV can maintain the control of viral replication after stopping the antiviral agent.…”

Section: H Epatitis B Virus (Hbv) Is a Noncytopathic Dnamentioning

confidence: 99%

Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity

et al. 2005

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H epatitis B virus (HBV) is a noncytopathic DNAvirus, which can cause acute, self-limited hepatitis or chronic hepatitis, cirrhosis, and/or hepatocellular carcinoma. 1 The diversity of clinical outcomes after exposure to HBV is determined primarily by the host immune response. 2,3 The resolution of HBV infection after acute self-limited hepatitis is associated with strong CD4ϩ and CD8ϩ T-cell responses, with a type 1 cytokine profile. [4][5][6][7] In contrast to this strong antiviral T-cell reactivity, which persists in the convalescent phase after hepatitis B surface antigen (HBsAg) clearance, patients with chronic HBV infection have weak or undetectable T-cell reactivity to HBV, which is the dominant factor that permits an ongoing, high level of viral replication. A series of investigations of the mechanisms by which Tcells control HBV replication showed the major role of cytokine-mediated, intracellular inactivation of HBV that does not require cell death. 8 This noncytolytic antiviral effect, first demonstrated in an HBV transgenic mouse model and subsequently in other animals, is primarily mediated by interferon-gamma (IFN-␥). 9-11 A detailed analysis of HBV clearance during acute infection in chimpanzees showed that the disappearance of viral DNA from the liver coincides with IFN-␥ induction before the increase of serum alanine aminotransferase (ALT), in other words, without destruction of hepatocytes. 11

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Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes

Cited by 46 publications

References 25 publications

CD8+ T Cell Control of Hepatitis B Virus Replication: Direct Comparison between Cytolytic and Noncytolytic Functions

CD8+ T Cell Control of Hepatitis B Virus Replication: Direct Comparison between Cytolytic and Noncytolytic Functions

The role of cells refractory to productive infection in acute hepatitis B viral dynamics

Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity

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