Control of Viremia and Prevention of AIDS following Immunotherapy of SIV-Infected Macaques with Peptide-Pulsed Blood

Rose, Robert De; Fernandez, Caroline S.; Smith, Miranda; Batten, C. Jane; Alcântara, Sheilajen; Peut, Vivienne Mary; Rollman, Erik; Loh, Liyen; Mason, Rosemarie D.; Wilson, Kim; Law, Matthew; Handley, Amanda; Kent, Stephen J.

doi:10.1371/journal.ppat.1000055

Cited by 49 publications

(65 citation statements)

References 36 publications

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“…Three macaques participated in a replicon-based SIV vaccine trial that failed to provide any protective immunity (15) and had been infected with SIV mac251 32 weeks previously. Nine SIV-infected macaques were part of a previous peptide-pulsed blood cell vaccine study (11) and had been infected with SIV mac251 87 weeks previously. The 12 animals were randomized into two groups, the IPAL treatment (n ϭ 6) and control (n ϭ 6) groups, stratified by viral load, CD4 T-cell counts, weight, MHC class-I Mane-A*10 expression, and prior Gag-specific CD4 and CD8 T-cell responses.…”

Section: Animalsmentioning

confidence: 99%

“…IPAL animals were immunized with a modified OPAL immunotherapy (11). PBMC were isolated over Ficoll-Paque from 9-ml whole-blood samples collected in Na-heparin-treated Vacuette tubes.…”

Section: Animalsmentioning

confidence: 99%

“…Since many of the animals used in the IPAL study had been study subjects in previous OPAL studies (10,11), in post hoc analyses, we were able to directly compare the magnitude of SIV Gag-specific CD4 ϩ and CD8 ϩ responses following IPAL vaccination with those observed following prior OPAL vaccinations. Immunization with IPAL induced CD4 ϩ T-cell responses to SIV Gag to a magnitude that was similar to that observed with OPAL immunization using Gag peptides and was greater than that observed with OPAL using peptides spanning all SIV proteins (11) (Fig. 7A).…”

Section: Analysis Of Cd4mentioning

confidence: 99%

“…We have shown that overlapping peptide-pulsed autologous PBMC (OPAL) immunotherapy for SIV-infected monkeys, administered along with antiretroviral therapy (ART), is a safe and effective treatment for boosting SIV-specific T-cell responses and significantly reducing viral load following vaccination when ART is withdrawn (11). However, to adequately cover important protein targets for an outbred population with highly polymorphic major histocompatibility complex (MHC) alleles, a large number of peptides needs to be manufactured and pooled.…”

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confidence: 99%

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Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

Mason

Alcântara

Peut

et al. 2009

J Virol

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Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIV mac251 infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4 ؉ T-cell responses (mean, 5.9% ؎ 1.3% of all CD4 ؉ T cells) and to a lesser extent SIV-specific CD8 ؉ T-cell responses (mean, 0.7% ؎ 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4 ؉ T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4 ؉ T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide-pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted.

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Section: Animalsmentioning

confidence: 99%

“…IPAL animals were immunized with a modified OPAL immunotherapy (11). PBMC were isolated over Ficoll-Paque from 9-ml whole-blood samples collected in Na-heparin-treated Vacuette tubes.…”

Section: Animalsmentioning

confidence: 99%

Section: Analysis Of Cd4mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

Mason

Alcântara

Peut

et al. 2009

J Virol

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“…While emphasis has been placed on evaluating immunity to prophylactic vaccines, no studies to our knowledge have addressed the nature of the immune response to Ad-based vaccination in established HIV infection. This is an important consideration given the interest in therapeutic vaccination as a means of controlling HIV [21][22][23][24][25]. In addition to enhancing the magnitude and polyfunctional nature of Ag-specific CD4 [30,31].…”

Section: Introductionmentioning

confidence: 99%

Adenovirus 5‐ and 35‐based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection

et al. 2009

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Heterologous adenovirus-based vectors hold promise as preventative HIV vaccines but their capacity to induce effective T-cell immunity in established infection has not been explored. We vaccinated rhesus macaques chronically infected with SIVmac251 and undergoing antiretroviral therapy (ART) with human adenovirus serotype 5-based vectors expressing SIV Gag, Env, and Nef with and without IL-15 and evaluated vaccine immunogenicity. Vaccination increased Ag-specific T cells 20-fold but did not expand the breadth of epitopes recognized or the quality of response, as the majority of CD8 1 and CD4 1 T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4 1 central memory T cells (Tcm) and boosted CD4 1 and CD81 Tcm and effector cell responses but did not prevent virus rebound upon cessation of ART. Boosting with human adenovirus serotype 35-based vectors during a second ART cycle increased Ag-specific T cells to 50-fold above pre-vaccination levels and boosted CD4 1 Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4 1 Tcm correlated positively with complexity of T-cell responses and negatively with virus load, suggesting that more complete restoration of this subset through vaccination would be beneficial.Key words: Cellular immunology . HIV . Vaccination . Virology IntroductionAdenovirus (Ad)-based vectors have arisen as leading vaccine candidates for the prevention of HIV infection [1][2][3] based on studies in rhesus macaques demonstrating robust immunogenicity and control of infection with SIV/HIV hybrid viruses and the pathogenic SIVmac251 strain [4][5][6]. However, the recent failure of the Merck Phase IIB STEP trial of a replication-defective human adenovirus serotype 5 (Ad5)-based vaccine against HIV in humans has raised concerns over the nature of the immune response induced by these vectors [7][8][9] and has placed renewed emphasis on nonhuman primate models to address this issue Eur. J. Immunol. 2009. 39: 2437-2449 DOI 10.1002 Immunity to infection 2437 [10]. Mounting evidence suggests that the quality of the T-cell response may be as important as the magnitude of this response in containing infection [11], with durable control of HIV associated with Ag-specific CD4 1 and CD8 1 T cells producing multiple cytokines and chemokines [12][13][14][15]. Immunogenicity studies indicate that Ad5-based vectors promote restricted cellular immunity consisting of CD8 1 T-cell-dominated responses devoid of IL-2 production [16][17][18]. In contrast, combining Ad5 with rare heterologous Ad-based vectors increases the magnitude, breadth, and quality of vaccine-induced T-cell response and significantly controls SIV infection in monkeys [6,17]. These and other studies in mice [19,20] suggest that prime-boost vaccine strategies that combine Ad5 with other viral vectors may be effective at generating superior T-cell responses against HIV. While emphasis has been placed on evaluating...

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HIV Immunology and Prospects for Vaccines

Jülg

Walker

2009

AIDS and Tuberculosis

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Control of Viremia and Prevention of AIDS following Immunotherapy of SIV-Infected Macaques with Peptide-Pulsed Blood

Cited by 49 publications

References 36 publications

Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

Adenovirus 5‐ and 35‐based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection

HIV Immunology and Prospects for Vaccines

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