Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

Shata, Mohamed T.; Tricoche, Nancy; Perkus, Marion E.; Tom, Darley; Brotman, Betsy; McCormack, Patricia; Pfahler, Wolfram; Lee, Dong Hun; Tobler, Leslie H.; Busch, Michael P.; Prince, Alfred M.

doi:10.1016/s0042-6822(03)00461-6

Cited by 70 publications

(73 citation statements)

References 65 publications

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“…No healthy controls (0 of 20) mounted a significant response to any HCV-specific antigen (mean SI core , 1.0; SI NS3 , 0.8; SI NS4 , 0.9; SI NS5 , 0.8 [data not shown]). CD4 ϩ and CD8 ϩ depletion assays performed as previously described (29,30), using paramagnetic microbeads conjugated to a monoclonal mouse anti-human anti-CD8 ϩ or anti-CD4 ϩ antibody (Micro Beads), showed that proliferative responses are mediated by CD4 ϩ cells (data not shown).…”

Section: Methodsmentioning

confidence: 94%

“…The CD4 ϩ or CD8 ϩ T-cell populations were isolated from the PBMC by positive selection using paramagnetic microbeads conjugated to a monoclonal mouse anti-human anti-CD8 ϩ or anti-CD4 ϩ antibody (Micro Beads; Miltenyl Biotec, Bergisch Gladbach, Germany) as previously described (29,30). The viability and purity of isolated CD4 ϩ or CD8 ϩ T-cell populations were checked by flow cytometry, which revealed more than 95% purity.…”

Section: Methodsmentioning

confidence: 99%

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Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

Kamal

Amin²,

Madwar³

et al. 2004

J Virol

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Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion.Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4؉ and CD8؉ cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4؉ and CD8؉ responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development.Hepatitis C virus (HCV) is a frequent cause of liver disease, leading to chronic infection in as many as 170 million persons worldwide. Vaccine development for HCV, like that for human immunodeficiency virus type 1 (HIV-1), is limited by the quasispecies nature of the virus as well as a lack of clear evidence that humoral immune responses protect against infection. Unlike patients with HIV-1, some individuals infected with acute hepatitis C can recover, although the asymptomatic nature of acute infection in most infected persons and the relative difficulty in conducting prospective studies have limited our understanding of the correlates of recovery from infection. Therefore, most studies have relied upon retrospective identification of subjects who previously cleared HCV to ascertain the correlates of protective immunity. These studies have shown that vigorous polyclonal cellular immune responses are associated with spontaneous recovery, whereas chronic infection is associated with a less vigorous immune response in the peripheral blood and liver (2,6,9,11,19,22,31). The only animal model of HCV infection, the chimpanzee, has provided additional valuable insights into the importance of both CD4 ϩ and CD8 ϩ responses in controlling infection (4,8,30). However, the small numbers of individuals who can be identified as having spontaneous recovery and the retrospective nature of such studies may underestimate the true rates of clearance.The major risk factor for transmission of HCV is percutaneous or parenteral exposure to infected blood or blood products. However, sexual transmission may play a role in some cases, although the exact extent to which this is true and the precise determinants of transmission are as yet unknown. In this study we took a...

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Section: Methodsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

Kamal

Amin²,

Madwar³

et al. 2004

J Virol

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“…CMI responses to sub-clinical infection without seroconversion have been reported in HCV Freeman et al, 2004;Post et al, 2004;Semmo et al, 2005;Shata et al, 2003b), and HIV (Alimonti et al, 2006;Clerici and Shearer, 1996;Dittmer et al, 1996;Fowke et al, 1996;Kaul et al, 2004) infections. Memory CMI responses are also long lasting and could be detected up to 20-30 years after exposure despite the decrease of humoral immune responses.…”

Section: Introductionmentioning

confidence: 94%

“…To estimate the number of HEV-specific interferon-γ secreting cells (ISC), PBMC were added at different concentrations (10 4 -10 5 cells/well) in a 100 μl volume of complete medium (RPMI-1640 containing 10% AB + serum). For stimulation, PBMC were pulsed with the test peptides or HEV ORF2 protein at 1-5 μg/ml as described (Shata et al, 2002(Shata et al, ,2003b. After an 18-hour incubation at 37 °C, the plates were washed 5 times with washing buffer (PBS containing 0.5% (v/v) Tween 20; Sigma, St. Louis, MO).…”

Section: Interferon-γ Elispot Assaymentioning

confidence: 99%

Characterization of hepatitis E-specific cell-mediated immune response using IFN-γ ELISPOT assay

Shata

Barrett

Shire

et al. 2007

Journal of Immunological Methods

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In developing countries, hepatitis E (HEV) and hepatitis A (HAV) are the major causes of acute viral hepatitis with similar fecooral modes of transmission. In contrast to the high seroprevalence of hepatitis A infection, a low seroprevalence of HEV among children in endemic areas has been reported. These data suggest the possibility that silent HEV infection is undiagnosed by the current available methods. Many of the serological tests used for HEV diagnosis have poor specificity and are unable to differentiate among different genotypes of HEV. Moreover, the RT-PCR used for HEV isolation is only valid for a brief period during the acute stage of infection. Cell-mediated immune (CMI) responses are highly sensitive, and long lasting after sub-clinical infections as shown in HCV and HIV. Our objective was to develop a quantitative assay for cell-mediated immune (CMI) responses in HEV infection as a surrogate marker for HEV exposure in silent infection. Quantitative assessment of the CMI responses in HEV will also help us to evaluate the role of CMI in HEV morbidity. In this study, an HEV-specific interferon-gamma (IFN-γ) ELISPOT assay was optimized to analyze HEV-specific CMI responses. We used peripheral blood mononuclear cells (PBMC) and sera from experimentally infected chimpanzees and from seroconverted and control human subjects to validate the assay. The HEV-specific IFN-γ ELISPOT responses correlated strongly and significantly with anti-HEV ELISA positive/negative results (rho=0.73, p=0.02). Moreover, fine specificities of HEV-specific T cell responses could be identified using overlapping HEV ORF2 peptides.

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“…56 In fact, there exists a subpopulation of individuals exposed to HCV that clear the virus without the induction of anti-HCV antibodies; therefore, the only surrogate markers for HCV exposure in such persons are HCV-specific cell-mediated immune responses. [57][58][59][60][61][62][63] …”

Section: Humoral Immune Responsesmentioning

confidence: 99%

Acute hepatitis C virus infection: A chronic problem

et al. 2007

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S ince the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion of information regarding its natural history, treatment, and replication cycle. Nonetheless, there are still relatively few data regarding acute HCV infection. By convention, the term acute hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6 months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion patients who developed non-A, non-B hepatitis provide a clinical picture of early infection. 1 Following the availability of specific serologic and virologic tests, most such patients were shown to have acute HCV infection. After acute infection, HCV RNA may become detectable in the serum/plasma in as little as 2 weeks ( Fig. 1). Several weeks later, a high percentage of patients experience an increase in serum aminotransferase levels consistent with the development of acute hepatocellular injury. In the majority of cases, patients develop mild constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue. During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority-but not all-of infected patients, HCV RNA persists, and a chronic disease state develops.The reasons for the general lack of data regarding acute HCV infection are multifactorial and include (1) the relatively high percentage of asymptomatic or unrecognized early infections, (2) the lack of large-scale identification of chronic carriers in the general population who serve as a reservoir for infection, and (3) the decreased number of acute infections that occur in controlled clinical settings such as that of blood transfusions. These factors and the lack of nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the use of limited historical collections of banked sera, and the extrapolation of outcomes based on small disease outbreaks in unique settings (for example, transmission from a physician to a patient in the operating room setting or following parenteral exposure in healthcare workers). Moreover, there exist only a limited number of population cohorts that continue to experience high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of information regarding the clinical presentation, natural history, and treatment outcomes of acute HCV infection.In this article, we review the current information regarding our understanding of the epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV infection. In addition, we review recent data related to interferon-based treatment intervention and propose an algorithm for the diagnosis and management of acute HCV inf...

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Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

Cited by 70 publications

References 65 publications

Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

Characterization of hepatitis E-specific cell-mediated immune response using IFN-γ ELISPOT assay

Acute hepatitis C virus infection: A chronic problem

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