Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production

Betts, Michael R.; Casazza, Joseph P.; Koup, Richard A.

doi:10.1016/s0165-2478(01)00273-5

Cited by 54 publications

(36 citation statements)

References 19 publications

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“…Earlier reports have found a correlation between disease progression and CTL responses towards certain HIV proteins (32,39,48), but more recent studies using comprehensive screening techniques fail to confirm this (1,11,37). Although the subjects in the present study are more advanced in their disease course than cohorts studied before, data presented here are in accordance with the latter observation, as differences to controllers were not statistically significant.…”

Section: Discussionsupporting

confidence: 81%

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

Draenert

Verrill

Tang

et al. 2004

J Virol

128

115

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CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load ‫؍‬ 142,000 copies/ml; median CD4 count ‫؍‬ 71/l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10 6 peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P ‫؍‬ 0.032) and magnitude (P ‫؍‬ 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferonpositive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

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Section: Discussionsupporting

confidence: 81%

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

Draenert

Verrill

Tang

et al. 2004

J Virol

128

115

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“…This is lower than typically observed in other chronic viral infections such as in HIV-1, where the magnitude of HIV-1-specific IFN-␥ ϩ CD8 ϩ T cells ranges from 0.8% to 18.0%. 12,17 The magnitude of intrahepatic cytokine ϩ HBV-specific T cells was similar to that seen in cultured PBMC (0.0%-1.80%). The low magnitude of HBV-specific T cells found in blood was therefore not explained by sequestration of HBV-specific T cells to the liver, which has been previously shown to be true in both HBV and HCV infections when using virus-specific tetramer ϩ T cells.…”

Section: Discussionsupporting

confidence: 54%

“…ICS was performed on whole blood as previously described, 4,11,12 with some minor modifications to include anti-IFN-␥-fluorescein isothiocyanate (clone B27) and anti-tumor necrosis factor-␣-Allophycocyanin (MAb11) or anti-interleukin-2 (IL-2)-fluorescein isothiocyanate (clone MQ1-17H12) and anti-interleukin-10 (IL-10)-Allophycocyanin (clone JES3-19F1; all from BD Biosciences). The same ICS method was also used with expanded PBMCs and LILs resuspended at 1 ϫ 10 6 cells/well in 200 l RPMI 1640, 10% human AB serum, and penicillin/streptomycin/glutamine.…”

Section: Methodsmentioning

confidence: 99%

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

et al. 2007

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H epatitis B virus (HBV)-specific T cells are im-portant in the successful clearance of acute HBV infection but also mediate liver damage in both acute and chronic HBV infections. In individuals with chronic HBV infection, circulating HBV-specific T cells are detected infrequently and are significantly reduced compared with individuals who recover from acute HBV infection. [1][2][3] We recently developed a sensitive method to assess HBV-specific T cells using an overlapping peptide library and intracellular cytokine staining (ICS). 4 However, despite detection of interferon-gamma (IFN-␥) HBV-specific T cells in blood, the magnitude of CD4 ϩ and CD8 ϩ HBV-specific T cells in chronic HBV infection was still significantly lower than that observed in other chronic infections such as human immunodeficiency virus (HIV)-1. 3,4 Previous studies using tetramer staining suggested a larger population of HBV-specific T cells being sequestered within the liver than in circulation. 2,5,6 Although a useful tool to quantify virus-specific T cells, the use of tetramers will detect virus-specific T cells regardless of their function or ability to produce cytokine. 7 In addition,

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“…Intracellular cytokine staining (ICS) was performed as previously described (8,9,34,43) with some minor modifications. Briefly, whole blood was collected in sodium heparin tubes and prepared for peptide stimulation either on the day of collection or after keeping blood at room temperature overnight.…”

Section: Methodsmentioning

confidence: 99%

Reduced Hepatitis B Virus (HBV)-Specific CD4⁺T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy

Chang

Wightman

Bartholomeusz

et al. 2005

J Virol

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Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronicallyinfected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4 ؉ and CD8 ؉ T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n ‫؍‬ 34) were studied, including individuals never treated for HBV infection (n ‫؍‬ 7), HBV-infected individuals receiving anti-HBV therapy (n ‫؍‬ 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n ‫؍‬ 14). CD4؉ and CD8 ؉ HBV-specific T-cell responses were more frequently detected and the CD8 ؉ T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBVspecific T-cell response and HBV viral load. HBV-specific CD4؉ and CD8 ؉ T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8 ؉ T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4 ؉ T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.There are 350 million individuals chronically infected with hepatitis B virus (HBV) worldwide (36,42,59). Each year 1 million to 1.5 million carriers die from HBV-related liver disease and liver cancer such as hepatocellular carcinoma (36,48). In the United States, Europe, and Australia, approximately 6 to 7% of individuals infected with human immunodeficiency virus type 1 (HIV-1) are also coinfected with HBV (23, 41). Liver disease is now a major comorbidity in HIV-1-infected individuals (11,66). Although hepatitis C virus (HCV)-HIV-1 coinfection is more common than HBV infection, liver failure occurs more frequently with persistent HBV infection (60, 63). Coinfection of HBV with HIV-1 leads to elevated HBV DNA levels, a lower rate of seroconversion to HBeAg, and lower alanine aminotransferase (ALT) levels than those in HBV monoinfection (21, 31). Spontaneous flares and HBeAg seroconversion occur in 5% of HBV-monoinfected individuals; however, in the setting of HIV-1-HBV coinfection, spontaneous flares or seroconversion to HBeAg is rare (18). In individuals infected with HIV-1 who subsequently acquire HBV infection, there is an increased risk of persisten...

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Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production

Cited by 54 publications

References 19 publications

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

Reduced Hepatitis B Virus (HBV)-Specific CD4⁺T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy

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Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production

Cited by 54 publications

References 19 publications

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

Reduced Hepatitis B Virus (HBV)-Specific CD4+T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy

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Product

Resources

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Reduced Hepatitis B Virus (HBV)-Specific CD4⁺T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy