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HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function

Appay, Victor ; Nixon, Douglas F. ; Donahoe, Sean M. ; [et al.]

Rockefeller University Press ; 2000

In: The Journal of Experimental Medicine Vol. 192, No. 1 ( 2000-07-03), p. 63-76

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In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 192, No. 1 ( 2000-07-03), p. 63-76

Abstract: The use of peptide–human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8+ T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8+ T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, and perforin is analyzed by FACS® within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8+ T cells compared with cytomegalovirus (CMV)-specific CD8+ T cells in HIV chronic infection. We show that the majority of circulating CD8+ T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-γ and MIP-1β but not TNF-α. However, a striking finding is that HIV-specific CD8+ T cells express significantly lower levels of perforin than CMV-specific CD8+ T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8+ T cells are impaired in cytolytic activity.

Type of Medium: Online Resource

ISSN: 0022-1007 , 1540-9538

URL: Article

DOI: 10.1084/jem.192.1.63

RVK:

XA 10000

Language: English

Publisher: Rockefeller University Press

Publication Date: 2000

detail.hit.zdb_id: 1477240-1

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A Plea for Justice for Jailed Medical Workers

Ahuja, Sunil K. ; Aiuti, Fernando ; Berkhout, Ben ; [et al.]

American Association for the Advancement of Science (AAAS) ; 2006

In: Science Vol. 314, No. 5801 ( 2006-11-10), p. 924-925

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In: Science, American Association for the Advancement of Science (AAAS), Vol. 314, No. 5801 ( 2006-11-10), p. 924-925

Type of Medium: Online Resource

ISSN: 0036-8075 , 1095-9203

URL: Article

DOI: 10.1126/science.1136578

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: American Association for the Advancement of Science (AAAS)

Publication Date: 2006

detail.hit.zdb_id: 128410-1

detail.hit.zdb_id: 2066996-3

detail.hit.zdb_id: 2060783-0

SSG: 11

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Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

Fischer, Will ; Ganusov, Vitaly V. ; Giorgi, Elena E. ; [et al.]

Public Library of Science (PLoS) ; 2010

In: PLoS ONE Vol. 5, No. 8 ( 2010-8-20), p. e12303-

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In: PLoS ONE, Public Library of Science (PLoS), Vol. 5, No. 8 ( 2010-8-20), p. e12303-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0012303

DOI: 10.1371/journal.pone.0012303.g001

DOI: 10.1371/journal.pone.0012303.g002

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DOI: 10.1371/journal.pone.0012303.s015

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2010

detail.hit.zdb_id: 2267670-3

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Comparative Immunogenicity of HIV-1 Clade C Envelope Proteins for Prime/Boost Studies

Smith, Douglas H. ; Winters-Digiacinto, Peggy ; Mitiku, Misrach ; [et al.]

Public Library of Science (PLoS) ; 2010

In: PLoS ONE Vol. 5, No. 8 ( 2010-8-11), p. e12076-

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In: PLoS ONE, Public Library of Science (PLoS), Vol. 5, No. 8 ( 2010-8-11), p. e12076-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0012076

DOI: 10.1371/journal.pone.0012076.g001

DOI: 10.1371/journal.pone.0012076.g002

DOI: 10.1371/journal.pone.0012076.t001

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DOI: 10.1371/journal.pone.0012076.s001

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DOI: 10.1371/journal.pone.0012076.s003

DOI: 10.1371/journal.pone.0012076.s004

DOI: 10.1371/journal.pone.0012076.s005

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2010

detail.hit.zdb_id: 2267670-3

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A novel human CD4+ T-cell inducer subset with potent immunostimulatory properties

Ndhlovu, Lishomwa C. ; Leal, Fabio E. ; Eccles-James, Ijeoma G. ; [et al.]

Wiley ; 2009

In: European Journal of Immunology Vol. 40, No. 1 ( 2009-10-28), p. 134-141

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In: European Journal of Immunology, Wiley, Vol. 40, No. 1 ( 2009-10-28), p. 134-141

Type of Medium: Online Resource

ISSN: 0014-2980

URL: Article

DOI: 10.1002/eji.200939258

RVK:

XA 10000

Language: English

Publisher: Wiley

Publication Date: 2009

detail.hit.zdb_id: 1491907-2

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Vaccination with Cancer- and HIV Infection-Associated Endogenous Retrotransposable Elements Is Safe and Immunogenic

Sacha, Jonah B. ; Kim, In-Jeong ; Chen, Lianchun ; [et al.]

The American Association of Immunologists ; 2012

In: The Journal of Immunology Vol. 189, No. 3 ( 2012-08-01), p. 1467-1479

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 3 ( 2012-08-01), p. 1467-1479

Abstract: The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis and literature precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 open reading frame 2 induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human LINE-1 open reading frame 2 (96% identity with macaque), as well as simian endogenous retrovirus-K Gag and Env, induced polyfunctional T cell responses to all Ags, and Ab responses to simian endogenous retrovirus-K Env. There were no adverse safety or pathological findings related to vaccination. These studies provide the first evidence, to our knowledge, that immune responses can be induced safely against this class of self-antigens and pave the way for investigation of them as HIV- or tumor-associated targets.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.1200079

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2012

detail.hit.zdb_id: 1475085-5

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Highly Effective Control of an AIDS Virus Challenge in Macaques by Using Vesicular Stomatitis Virus and Modified Vaccinia Virus Ankara Vaccine Vectors in a Single-Boost Protocol

Ramsburg, Elizabeth ; Rose, Nina F. ; Marx, Preston A. ; [et al.]

American Society for Microbiology ; 2004

In: Journal of Virology Vol. 78, No. 8 ( 2004-04-15), p. 3930-3940

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In: Journal of Virology, American Society for Microbiology, Vol. 78, No. 8 ( 2004-04-15), p. 3930-3940

Abstract: Previous studies have shown that vaccination and boosting of rhesus macaques with attenuated vesicular stomatitis virus (VSV) vectors encoding Env and Gag proteins of simian immunodeficiency virus-human immunodeficiency virus (SHIV) hybrid viruses protect rhesus macaques from AIDS after challenge with the highly pathogenic SHIV 89.6P (23). In the present study, we compared the effectiveness of a single prime-boost protocol consisting of VSV vectors expressing SHIV Env, Gag, and Pol proteins to that of a protocol consisting of a VSV vector prime followed with a single boost with modified vaccinia virus Ankara (MVA) expressing the same SHIV proteins. After challenge with SHIV 89.6P, MVA-boosted animals controlled peak challenge viral loads to less than 2 × 10 6 copies/ml (a level significantly lower than that seen with VSV-boosted animals and lower than those reported for other vaccine studies employing the same challenge). MVA-boosted animals have shown excellent preservation of CD4 + T cells, while two of four VSV-boosted animals have shown significant loss of CD4 + T cells. The improved protection in MVA-boosted animals correlates with trends toward stronger prechallenge CD8 + -T-cell responses to SHIV antigens and stronger postchallenge SHIV-neutralizing antibody production.

Type of Medium: Online Resource

ISSN: 0022-538X , 1098-5514

URL: Article

DOI: 10.1128/JVI.78.8.3930-3940.2004

Language: English

Publisher: American Society for Microbiology

Publication Date: 2004

detail.hit.zdb_id: 1495529-5

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CCL3L1-CCR5 Genotype Improves the Assessment of AIDS Risk in HIV-1-Infected Individuals

Kulkarni, Hemant ; Agan, Brian K. ; Marconi, Vincent C. ; [et al.]

Public Library of Science (PLoS) ; 2008

In: PLoS ONE Vol. 3, No. 9 ( 2008-9-8), p. e3165-

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In: PLoS ONE, Public Library of Science (PLoS), Vol. 3, No. 9 ( 2008-9-8), p. e3165-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0003165

DOI: 10.1371/journal.pone.0003165.g001

DOI: 10.1371/journal.pone.0003165.g002

DOI: 10.1371/journal.pone.0003165.g003

DOI: 10.1371/journal.pone.0003165.t001

DOI: 10.1371/journal.pone.0003165.t002

DOI: 10.1371/journal.pone.0003165.s001

DOI: 10.1371/journal.pone.0003165.s002

DOI: 10.1371/journal.pone.0003165.s003

DOI: 10.1371/journal.pone.0003165.s004

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2008

detail.hit.zdb_id: 2267670-3

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Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial

Kuebler, Peter J. ; Mehrotra, Megha L. ; McConnell, J. Jeff ; [et al.]

Proceedings of the National Academy of Sciences ; 2015

In: Proceedings of the National Academy of Sciences Vol. 112, No. 27 ( 2015-07-07), p. 8379-8384

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 27 ( 2015-07-07), p. 8379-8384

Abstract: HIV-1–specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case–control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1–negative for Gag ( P = 0.007), Integrase ( P 〈 0.001), Vif ( P 〈 0.001), and Nef ( P 〈 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19–0.66 and HR = 0.52, 95% CI = 0.28–0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1–specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1501443112

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2015

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

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Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection

Shacklett, Barbara L. ; Cox, Catherine A. ; Quigley, Máire F. ; [et al.]

The American Association of Immunologists ; 2004

In: The Journal of Immunology Vol. 173, No. 1 ( 2004-07-01), p. 641-648

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 173, No. 1 ( 2004-07-01), p. 641-648

Abstract: Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-γ upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.173.1.641

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2004

detail.hit.zdb_id: 1475085-5

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