Long-Lasting Decrease in Viremia in Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 after Therapeutic DNA Immunization

Gegerfelt, Agneta S. von; Rosati, Margherita; Alicea, Candido; Valentı́n, Antonio; Roth, Patricia; Bear, Jenifer; Franchini, Genoveffa; Albert, Paul S.; Bischofberger, Norbert; Boyer, Jean; Weiner, David B.; Markham, Phillip D.; Israel, Zimra R.; Eldridge, John H.; Pavlakis, George N.; Felber, Barbara K.

doi:10.1128/jvi.01990-06

Cited by 39 publications

(65 citation statements)

References 37 publications

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“…During the chronic phase, immune control is important, and small changes in the number of effector cells can have a large effect in the model. Increasing the number of CD8 ϩ T cells by therapeutic vaccination (58,94) or depleting them with a monoclonal antibody (46,67,85) during the chronic phase of the infection indeed markedly affects the viral load. The former is surprising because one would expect a minor effect of therapeutic vaccination, since there is enough antigen available to stimulate the CD8 ϩ T cells.…”

Section: Prophylactic Vaccinationmentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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Although CD8 ؉ T cells play an important role in controlling viral infections, boosting specific CD8 ؉ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8 ؉ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8 ؉ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8 ؉ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid-or protein-based vaccines.

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Section: Prophylactic Vaccinationmentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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“…The vaccination of HIV-1-infected individuals (67) or SIV-infected macaques (47,49,56,68) with these vaccine modalities results in an expansion of virus-specific adaptive CD4 ϩ and CD8 ϩ T cells that is nevertheless insufficient to control viral replication in the long term. In SIV mac251 -infected macaques we have previously demonstrated a correlation between vaccine-induced CD4 ϩ and CD8 ϩ T cell responses and set point viremia following ART suspension (49), and the phenotypic characterization of SIV-specific CD8 ϩ T cells demonstrated an inverse correlation with Ag-specific central memory CD8 ϩ T cells and plasma virus level (68).…”

Section: Discussionmentioning

confidence: 99%

“…The ability of therapeutic vaccines to expand memory CD4 ϩ T cell responses has been correlated with the transient control of viral replication (56). Thus, approaches able to further expand SIV-specific memory responses may synergize with vaccination.…”

Section: Il-15 Abrogates the Ability Of Vaccination To Decrease Plasmmentioning

confidence: 99%

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Hryniewicz

Price

Moniuszko

et al. 2007

The Journal of Immunology

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The loss of CD4+ T cells and the impairment of CD8+ T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIVmac251-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4+ or CD8+ memory T cells, clonal recruitment to the SIV-specific CD8+ T cell pool, or CD8+ T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4+ effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-β expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.

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“…Tcm are decimated may favor recovery of these cells and promote immunologic control of virus load following discontinuation of ART. Therapeutic vaccination given during 20 to 24 wk of ART in SIVmac251-infected macaques was successful in inducing virus control following termination of ART, although the effect of vaccination on CD4 1 Tcm was not reported [22,25].Ad-mediated expression of IL-15 in addition to viral genes may have had a detrimental effect on immune control of virus infection in our study, as animals in the Ad-SIV/IL-15 group tended to have lower IFN-g ELISPOT responses following vaccination along with higher virus loads following termination of ART relative to the Ad-SIV group. While not specifically addressed here, other studies have shown that IL-15 immunotherapy during SIV infection increases proliferation and activation of CD4…”

mentioning

confidence: 99%

“…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].…”

mentioning

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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Long-Lasting Decrease in Viremia in Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 after Therapeutic DNA Immunization

Cited by 39 publications

References 37 publications

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

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

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Long-Lasting Decrease in Viremia in Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 after Therapeutic DNA Immunization

Cited by 39 publications

References 37 publications

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

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

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Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus