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Ronald S Veazey, Paula M Acierno,
Kimberly J McEvers,
Susanne H C Baumeister,
Gabriel J Foster,
Melisa D Rett,
Michael H Newberg,
Marcelo J Kuroda,
Kenneth Williams,
Eun-Young Kim,
Steven M Wolinsky,
E Peter Rieber,
Michael Piatak,
Jeffrey D Lifson,
David C Montefiori,
Charles R Brown,
Vanessa M Hirsch,
Jörn E Schmitz
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ABSTRACT: Previously we have shown that CD8(+) T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4(+) T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8(+) T-cell responses on the magnitude of the CD4(+) T-cell depletion, we investigated the effect of CD8(+) lymphocyte depletion during primary SIV infection on CD4(+) T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8(+) lymphocyte-depletion changed the dynamics of CD4(+) T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4(+) T cells were restored to baseline levels. These CD4(+) T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8(+) lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5(+) CD45RA(-) CD4(+) T cells in CD8(+) lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4(+) T cells were eliminated more efficiently in CD8(+) lymphocyte-depleted animals. Also, CD8(+) lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4(+) T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8(+) T-cell responses are absolutely critical to initiate at least partial control of SIV infection.
Journal of Virology 07/2008; 82(11):5618-30. · 5.40 Impact Factor
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Paula M Acierno,
Jörn E Schmitz,
Darci A Gorgone,
Yue Sun,
Sampa Santra,
Michael S Seaman,
Michael H Newberg,
John R Mascola,
Gary J Nabel,
Dennis Panicali,
Norman L Letvin
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ABSTRACT: Functional impairment of virus-specific memory CD8(+) T lymphocytes has been associated with clinical disease progression following HIV, SIV, and simian human immunodeficiency virus infection. These lymphocytes have a reduced capacity to produce antiviral cytokines and mediators involved in the lysis of virally infected cells. In the present study, we used polychromatic flow cytometry to assess the frequency and functional capacity of central memory (CD28(+)CD95(+)) and effector memory (CD28(-)CD95(+)) subpopulations of Gag-specific CD8(+) T cells in SIV/simian human immunodeficiency virus-infected rhesus monkeys. The aim of this study was to determine whether Ag-specific, memory CD8(+) T cell function could be preserved in infected monkeys that had been immunized before infection with a vaccine regimen consisting of a plasmid DNA prime followed by a recombinant viral vector boost. We observed that vaccination was associated with the preservation of Gag-specific central memory CD8(+) T cells that were functionally capable of producing IFN-gamma, and effector memory CD8(+) T cells that were capable of producing granzyme B following viral Ag exposure.
The Journal of Immunology 06/2006; 176(9):5338-45. · 5.79 Impact Factor
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Yue Sun,
Jörn E Schmitz, Paula M Acierno,
Sampa Santra,
Ramu A Subbramanian,
Dan H Barouch,
Darci A Gorgone,
Michelle A Lifton,
Kristin R Beaudry,
Kelledy Manson,
Valerie Philippon,
Ling Xu,
Holden T Maecker,
John R Mascola,
Dennis Panicali,
Gary J Nabel,
Norman L Letvin
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ABSTRACT: Production of IL-2 and IFN-gamma by CD4+ T lymphocytes is important for the maintenance of a functional immune system in infected individuals. In the present study, we assessed the cytokine production profiles of functionally distinct subsets of CD4+ T lymphocytes in rhesus monkeys infected with pathogenic or attenuated SIV/simian human immunodeficiency virus (SHIV) isolates, and these responses were compared with those in vaccinated monkeys that were protected from immunodeficiency following pathogenic SHIV challenge. We observed that preserved central memory CD4+ T lymphocyte production of SIV/SHIV-induced IL-2 was associated with disease protection following primate lentivirus infection. Persisting clinical protection in vaccinated and challenged monkeys is thus correlated with a preserved capacity of the peripheral blood central memory CD4+ T cells to express this important immunomodulatory cytokine.
The Journal of Immunology 05/2005; 174(8):4753-60. · 5.79 Impact Factor
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ABSTRACT: Interest in semi-allogeneic vaccines has been increasing, as demonstrated by the publication of successful preclinical and clinical studies by others and us that validate this immunotherapeutic approach to cancer and HIV-infection. We now report that lymphocytes from an HLA-A2+ melanoma patient, stimulated with a GP100-derived epitope and semi-allogeneic hybrids, lysed target cells presenting this peptide more efficiently than lymphocytes stimulated with GP100 peptide alone. Phenotypic analysis with GP100/HLA-A2 tetramer complexes also demonstrated a significant increase in the size of the GP100-specific CD8+ lymphocyte pool when PBMC were stimulated with both peptide and semi-allogeneic hybrids. Analyses of PBMC from other donors further suggest that this stimulatory effect of semi-allogeneic hybrids results from an increase in the HLA-restricted recall response of CD8+ cytotoxic T lymphocytes against melanoma-derived antigens. Likewise, lymphocytes from an HIV-infected patient that had been stimulated with a mixture of HIV-derived peptides and semi-allogeneic hybrids also demonstrated significantly greater antigen-specific cytotoxicity and tetramer reactivity compared with those lymphocytes that had been stimulated with peptides alone. Our approach should provide useful information for the design of future clinical studies treating patients with melanoma or HIV with therapeutic vaccines consisting of a combination of semi-allogeneic hybrids and immunodominant antigenic peptides.
Journla of Immunotherapy 06/2002; 25(4):334-41. · 3.27 Impact Factor
