Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals

Cosma, Antonio; Nagaraj, Rashmi; Bühler, Silja; Hinkula, Jorma; Busch, Dirk H.; Sutter, Gerd; Goebel, F. D.; Erfle, Volker

doi:10.1016/s0264-410x(03)00538-3

Cited by 110 publications

(99 citation statements)

References 34 publications

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“…These data confirm our previous characterization of the T-cell response induced by the MVA-nef vaccine as measured by IFN-g-based ICS. 4 However, the weak CD8 T-cell response to the vaccine, previously observed in subjects V8 and V10, was not detected in this study. It is likely that the use of frozen material and the analysis of a limited number of time points might have affected the capacity to detect these weak changes in responses.…”

Section: Mva-nef Vaccination Increases the Magnitude Of The Total Nefcontrasting

confidence: 71%

“…A simple interferon (IFN)-g based intracellular cytokine staining (ICS) performed with freshly isolated cell material was used to characterize specific T-cell responses in the firstline analysis of the clinical trial. 4 However, as recent advances in polychromatic flow-cytometry technology revealed that the sole evaluation of IFN-g provides limited information on the quality of antigen-specific T-cell responses, [5][6][7][8] in this study, we used more sophis-ticated assays to evaluate complex functional patterns of T-cell immune response. A correlation between the presence of antigen-specific CD4 T cells coproducing multiple cytokines and nonprogressive chronic HIV-1 infection has been shown in several cross-sectional studies.…”

Section: Introductionmentioning

confidence: 99%

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MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

et al. 2010

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Several vaccination trials are evaluating the modified vaccinia virus Ankara (MVA) as a delivery vector in various clinical settings. In this paper, we present the reevaluation of a therapeutic vaccination trial in human immunodeficiency virus (HIV)-1-infected individuals treated with highly active antiretroviral therapy using MVA-expressing HIV-1 nef. Immunogenicity of MVA-nef was assessed using multicolor flow cytometry. Vaccine-induced polyfunctionality and proliferative capacity, which are associated with nonprogressive HIV-1 infection, were detectable by combining two immune assays. By means of short-term polychromatic intracellular cytokine staining, we observed a significant increase in polyfunctional Nef-specific CD4 T cells expressing interferong, interleukin (IL)-2 and CD154 after vaccination, whereas changes in the quality of CD8 T-cell response could not be observed. Only the additional use of a long-term polychromatic Carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay revealed vaccine-induced Nef-specific CD8, as well as CD4 T cells with proliferative capacity. The correlation between vaccine-induced IL-2 production by CD4 T cells and the increase in proliferating Nef-specific CD8 T cells suggests a causal link between these two functions. These results highlight the importance of combining sophisticated immunomonitoring tools to unravel concealed effects of immunological interventions and support the use of the poxvirus-derived MVA vector to stimulate highly functional HIV-1-specific T-cell responses. However, the clinical benefit of these functional T cells remains to be determined.

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Section: Mva-nef Vaccination Increases the Magnitude Of The Total Nefcontrasting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

et al. 2010

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Section: Discussionmentioning

confidence: 99%

“…While there is now substantial evidence that MVAvectored vaccines expressing antigens from pathogens other than HIV-1 can efficiently expand primed CD4 + T cells in HIV-uninfected human subjects [25,34,35], our data suggest that MVA.HIVA vaccination can stimulate HIV-1-specific T helper responses to a greater array of epitopes than those targeted by CD4 + T cells during chronic infection. In contrast, in earlier studies involving therapeutic vaccinations with an MVA vaccine expressing the HIV-1 nef gene, cellular responses to nef epitopes were boosted by immunisation but generated conflicting results with regard to amplification of T helper responses [36,37].Other therapeutic vaccination studies have shown that recombinant canarypox expressing HIV-1 proteins or with inactivated envelope-depleted HIV-1 could augment virus-specific IFN-c-secreting CD4 + T cells and/or CD4 + T cell proliferative responses in HAARTtreated subjects [21,[38][39][40], but the cytokine expression profile of responding cells was not examined. Since progression of HIV-1 infection is accompanied by a shift in cytokine expression of virus-specific CD4 + T cells from a polyfunctional response to production of IFN-c only, with variable restoration of functions during HAART, we sought to investigate possible effects of MVA.HIVA vaccinations on these parameters [5,41].…”

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confidence: 90%

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

et al. 2006

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Virus-specific CD4 + T cells with IL-2-secreting and/or proliferative capacity are detected readily in HIV-1-infected long-term nonprogressors and rarely in persons with untreated progressive infection. The contribution of these cells to viraemia control is uncertain, but this question might be addressed in clinical therapeutic vaccination studies. However, the quality of T helper responses induced by currently available HIV-1 vaccine candidates has not been explored in depth. We determined the effect of vaccination with modified vaccinia virus Ankara (MVA) expressing HIV-1 gag p24/p17 (MVA.HIVA) on HIV-1-specific CD4 + T cell responses in 16 chronically infected, highly active antiretroviral therapy (HAART)-treated subjects using CD8-depleted IFN-c ELISPOT assays, intracellular cytokine staining assays for IL-2 and IFN-c, and a CFSEbased proliferation assay. Gag-specific CD4 + T cell responses were significantly increased in magnitude and breadth after vaccination and targeted both known and new epitopes, several of which were also recognised by healthy HIV-uninfected volunteers immunised with the same vaccines. The frequencies of CD4 + T cells expressing IL-2 or IFN-c, alone or simultaneously, were also augmented. These findings indicate that functional virus-specific T helper cells can be boosted by vaccination in chronic HIV-1 infection. Further evaluation of their role in viraemia control is warranted. IntroductionThe rate of progression of HIV-1 infection to AIDS may be determined by the capacity for immunological recovery after early and extensive depletion of mucosal CD4 + T cells [1]. Highly active antiretroviral therapy (HAART) can restore CD4 + T cell-mediated responses to opportunistic pathogens, but maintenance of adequate CD4 + T cell counts requires lifelong antiretroviral therapy, which is associated with potentially serious adverse effects and is too costly for the majority of infected persons worldwide [2]. Furthermore, the capacity of HIV-1-specific CD4 + T cells to proliferate and secrete IL-2, characteristics which are typically preserved only in long-term nonprogressors, are not always restored after initiation of therapy, particularly when this is delayed beyond acute infection [3][4][5][6]. Loss of function may result from preferential infection of virus-specific cells by 7,8]. Enhancement of HIV-1-specific cellular responses by therapeutic vaccination in combination with fully suppressive antiretroviral therapy might be used to maintain HIV-1 control without continuous drug treatment [9]. While a critical role for virus-specific CD4 + T cells in the induction and maintenance of effective immunity against HIV-1 is inferred from animal models and other human virus infections such as hepatitis C, direct evidence for this is lacking [10][11][12][13][14]. In healthy macaques, CD4 + T cell proliferation and TNF-a secretion were induced by DNA-prime/poxvirus-boost vaccinations, and were inversely correlated with control of SIV replication following a pathogenic challenge [15]. In humans, cross-...

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“…The safety of MVA has been established after testing it in immuno-compromised primate models and clinically in HIV patients, without findings of persistence or the development of adverse reactions [53][54][55]. Although MVA has not been tested in humans post-transplant, there are no properties of the virus that suggest it would be problematic or generate pathology.…”

Section: Discussionmentioning

confidence: 99%

Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1

Wang

Rosa

et al. 2007

Vaccine

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CMV tegument protein pp65 and CMV immediate early gene product IE1 are both considered immunodominant targets of cell-mediated immunity (CMI) and potentially capable of controlling CMV infection. To better assess their role in host defense, we have constructed a novel MVA transfer vector named pZWIIA and generated a recombinant MVA (rMVA) expressing both full-length pp65 and exon4 of IE1 (pp65-IE1-MVA) at high levels, followed by the genetic removal of the bacterial marker gene used to distinguish recombinant forms. Immunogenicity evaluation indicates that pp65-IE1-MVA not only can induce robust primary CMI to both antigens in HLA A2.1 Tg mice, but also can stimulate vigorous expansion of memory T lymphocyte responses to pp65 and IE1 in PBMC of CMV-positive donors. These properties make the MVA-based vaccine ideal for the dual role of priming and boosting CMV-specific T cell immunity as a means to control CMV disease in recipients of hematopoietic cell or solid organ transplantation (HCT or SOT). pZWIIA alone or in combination with other MVA transfer vectors can be used to generate MVA based multiple-antigen vaccine which have application in vaccine development for a wide spectrum of infectious diseases and cancer.

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Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals

Cited by 110 publications

References 34 publications

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1

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Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals

Cited by 110 publications

References 34 publications

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1

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Product

Resources

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Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses