Incubation Phase of Acute Hepatitis B in Man: Dynamic of Cellular Immune Mechanisms

Abstract

After hepatitis B virus (HBV) infectionThe incubation period of a viral disease refers to the time between infection and the onset of symptoms, and has been believed to represent the phase of active viral replication before an effective host immune response. This period is generally long after infection with noncytopathic viruses such as hepatitis B virus (HBV), 1 in contrast to other viral diseases. [2][3][4] The development of symptoms, which may occur up to 6 months after HBV infection, 5 has been assumed to mark the onset of viral control by the immune system. 1 However, the observation of marked reductions in virus levels before liver injury in the chimpanzee model of HBV infection, 6 and of cytotoxic T lymphocyte (CTL)-mediated viral clearance in the absence of cytolysis, in a transgenic mouse model of HBV infection, 7 has challenged the evidence that HBV control is predominantly caused by CTL-mediated tissue injury. It is, therefore, possible that immunologic events important for the control of HBV may already be present during the long incubation phase of primary infection. However, patients are usually only diagnosed after the development of symptoms: thus, it has been difficult to study the relationship between viral dynamics and liver injury, and whether the incubation phase of HBV infection in humans represents a period of ongoing viral replication in the presence of a deficient immune response. 8 During a single-source outbreak of HBV infection, in which 30 patients were infected through a skin-piercing procedure known as autohemotherapy, 9 a number of patients were identified before the onset of clinical hepatitis. The recent development of immunologic techniques to directly quantify virusspecific lymphocytes, 10,11 enabling the dynamics of CD8 and CD4 responses during viral infections to be investigated, provided a unique opportunity to study the interaction among virus, clinical disease, and host immune responses from the incubation phase of acute HBV infection. PATIENTS AND METHODS Patients.Five patients (all women, mean age 54 years, range 37-71) were identified during the incubation phase of acute hepatitis B, and were longitudinally followed up through the course of the disease. Their infection was diagnosed on the basis of finding a positive serum hepatitis B surface antigen (HBsAg), HBV DNA by polymerase chain reaction, normal or minimally raised serum alanine transaminase (ALT) levels, a marker of hepatocyte damage, 12 and no symptoms of clinical acute hepatitis. Each patient was infected with the same variant of HBV, as assessed by viral genome sequencing and

Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

“…Our findings indicate that CHB patients have T-cell failure. The same finding has also been demonstrated previously, namely, that the chronicity of HBV infection is caused by a deficiency in cellular immune function [16][17][18][19][20] , and hepatocyte damage is mainly caused by immunological injur y [21][22][23][24][25][26][27][28][29] . However, the mechanism has not been defined [5] .…”

“…Hepatocyte damage may also be correlated directly with T-cell failure, rather than through the load copies of viral replication. Previous studies have suggested that hepatocyte damage is mainly caused by immunological injury [9,[21][22][23][24][25][26][27][28][29][30] . HBV is a typical non-cytopathic virus that can induce tissue damage of variable severity by stimulating a protective immune response that can simultaneously cause damage and protection, by killing an intracellular virus through the destruction of virus-infected cells [5] .…”

B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B

“…During the natural course of HBV infection, patients with self-limited acute hepatitis B may develop strong virus-specific CD8 and CD4 T cell responses, although these T cell immune responses against the virus are insufficient to control infection in chronic hepatitis B (CHB) carriers (2)(3)(4). The mechanisms underlying this defect of specific T cell immunity have not yet been fully elucidated.…”

DNA-guided hepatitis B treatment: Viral load is insufficient with few exceptions

“…Low or undetectable DNA levels were seen in acute hepatitis [3] , whereas HBV DNA levels became detectable during reactivation of chronic hepatitis [4] . Kumar et al [5] in their study showed a low level of HBV DNA (< 0.5 pg/mL) in about 96% of patients with acute infection, as opposed to 13% in those with exacerbation of chronic hepatitis.…”

“…Using these criteria for antiviral therapy as stated by the guidelines, only 20%-60% of hepatocellular carcinoma (HCC) patients and 27%-70% of patients who died of non-HCC were identified for antiviral therapy. If the criteria were broadened with baseline serum albumin 3.5 gm/dL or less or platelet counts of 130 000 mm 3 or less, 89%-100% of deaths from non-HCC liver-related complications and 96%-100% HCC patients would be identified for antiviral therapy.…”