Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

Boni, Carolina; Bertoletti, Antonio; Penna, Amalia; Cavalli, A.; Pilli, Massimo; Urbani, Simona; Scognamiglio, Paola; Boehme, Richard; Panebianco, Ruggero; Fiaccadori, F; Ferrari, Carlo

doi:10.1172/jci3731

Cited by 447 publications

(372 citation statements)

References 30 publications

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Section: Figurementioning

confidence: 75%

“…Recent studies have suggested that suppression of HBV replication by lamivudine rapidly restores HBV-specific cellular immune responsiveness to the same level as in recovered persons (20). In that study, both CD4 ϩ (20) and CD8 ϩ (21) T cells specific for HBV remained detectable in the blood for up to 5 mo during lamivudine therapy. However, the increased T cell reactivity was not associated with an increase in loss of HBeAg or HBsAg (20), the serological hallmark of recovery from hepatitis B.…”

Section: Figurementioning

confidence: 75%

“…In that study, both CD4 ϩ (20) and CD8 ϩ (21) T cells specific for HBV remained detectable in the blood for up to 5 mo during lamivudine therapy. However, the increased T cell reactivity was not associated with an increase in loss of HBeAg or HBsAg (20), the serological hallmark of recovery from hepatitis B. Also, a second study of patients receiving IFN-␣ alone and in combination with lamivudine reported no restoration or de novo induction of HBV core-specific T cell proliferation (22).…”

Section: Figurementioning

confidence: 80%

“…Whereas some studies reported a restoration of HBV-specific T cell responses when persistently infected patients were treated with nucleoside analogs that inhibit HBV replication (20,21), these results have not been confirmed in other studies (22), and most treated patients do not maintain viral control (23,24). Thus, the hypothesis that high levels of HBV may suppress HBV-specific T cell responses is still controversial.…”

Section: T He Hepatitis B Virus (Hbv)mentioning

confidence: 98%

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Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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CD4+ T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8+ T cell and B cell responses. We have identified and characterized 10 CD4+ T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-γ ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-γ responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-γ production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p = 0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.

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Section: Figurementioning

confidence: 75%

Section: Figurementioning

confidence: 75%

Section: Figurementioning

confidence: 80%

Section: T He Hepatitis B Virus (Hbv)mentioning

confidence: 98%

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Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

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“…38,39 The treatment strategy in chronic hepatitis B aims to suppress HBV replication and to restore HBV-specific T-cell responses to achieve sustained remission. Suppression of HBV replication with an antiviral agent can enhance T-cell reactivity to HBV in some patients, 40 but this is transient 41,42 and does not occur in all patients. 43 Therefore, a combination of antiviral and immunomodulatory drugs is likely to be more successful.…”

Section: Discussionmentioning

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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Antiviral Agents, DNA

Middleton

Rockway

2003

Burger's Medicinal Chemistry and Drug Discovery

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The seven families of DNA viruses that cause disease in humans show tremendous variety in the relationships that they have with their hosts. This variety is reflected both in the disease states that they cause and the approaches used to develop antiviral drugs to treat them. The most successful antiviral tools have been nucleoside analogs, particularly those targeting the polymerases of herpesviruses and hepatitis virus B. The list of nucleoside analog drugs continues to expand as compounds are developed with greater potency or range, better bioavailability, or improved side effect profiles. Other viral targets have started to receive more attention, including helicases, proteases, and enzymes required for virion assembly. These targets should gain in importance as resistance to currently available drugs becomes more prevalent. In addition, expanding the list of viable viral targets is particularly important with regard to members of the parvovirus, papillomavirus, and polyomavirus families, which do not encode a viral polymerase. Some effective antiviral treatments have not targeted the virus but rather the immune response to the viral infection. An optimal immune response is critical to elimination of some classes of viruses, and exploiting this aspect of the host‐virus interaction provides another approach to antiviral drug development.

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Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

Cited by 447 publications

References 30 publications

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Lamivudine Plus Interleukin-12 Combination Therapy in Chronic Hepatitis B: Antiviral and Immunological Activity *

Antiviral Agents, DNA

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