Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8<sup>+</sup>T-Cell Epitopes

Goonetilleke, Nilu; Moore, S. S.; Dally, Len; Winstone, Nicola; Cebere, Inese; Mahmoud, Abdul; Pinheiro, Susana; Gillespie, Geraldine M.; Brown, Denise; Loach, Vanessa; Roberts, J. Timmons; Guimarães-Walker, A.; Hayes, Peter; Loughran, Kelley; Smith, Colton W; Bont, Jettie; Verlinde, C; Vooijs, Danii; Schmidt, Claudia; Boaz, Mark; Gilmour, Jill; Fast, Pat; Dorrell, Lucy; Hanke, Tomáš; McMichael, Andrew J.

doi:10.1128/jvi.80.10.4717-4728.2006

Cited by 217 publications

(179 citation statements)

References 79 publications

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“…Although significant progress has been made using DNA immunization to elicit HIV-1-specific CMI in small animals, non-human primates and humans over the past 15 years [12][13][14][15][16]18,[38][39][40][41], there has been no report of using Env DNA immunization to elicit broadly crossreactive antibodies in humans. Levels of anti-Env antibodies elicited in previous DNA vaccine clinical trials were either low or undetectable [42,43], nor was there a clear induction of NAbs against even sensitive viruses [14].…”

Section: Discussionmentioning

confidence: 99%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

124

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An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6−001 in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNγ ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cellmediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

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Section: Discussionmentioning

confidence: 99%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

124

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“…Three peptides had not been shown previously to contain T helper epitopes restricted by HLA alleles expressed by our vaccinees. Of note, six peptides (encompassing three regions) had also induced CD4 + T cell responses in healthy HIV-uninfected volunteers following primeboost immunisations with the same DNA and MVA vaccines [25]. This suggested that vaccination of HIV-1-infected individuals could stimulate CD4 + T cell responses to epitopes that were ignored during chronic infection.…”

Section: Resultsmentioning

confidence: 94%

“…Here, we have shown that these augmented responses were directed not only at epitopes known to be frequently targeted by HIV-1-infected persons but also new epitopes that were also recognised by HIV-uninfected subjects given this vaccine [24,25]. 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].…”

mentioning

confidence: 91%

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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“…Current HIV-1 DNA vaccines consist of one or more HIV genes whose expression is regulated by the CMV promoter. This type of DNA has been used for priming immunizations that are followed by boosts with viral vectors expressing HIV proteins (10,11). We have developed another type of DNA vaccine that was derived from the genome of a highly pathogenic simian HIV (SHIV), SHIV KU2 , from which the rt, int, vif, and the 3Ј long terminal repeat (LTR) were deleted.…”

mentioning

confidence: 99%

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

Arrode

Hegde

Mani

et al. 2007

The Journal of Immunology

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HIV DNA vaccines are potent inducers of cell-mediated immune (CMI) response in mice but elicit poor HIV-specific IFN-γ-producing T cells in monkeys and humans. In this study, we performed kinetic analyses on splenocytes of BALB/c mice that were immunized by a single injection with a unique DNA vaccine. Using IFN-γ-ELISPOT and multiparametric FACS analysis, we characterized the induced CMI response. We found that the response was detectable for at least 63 wk. ELISPOT detection of IFN-γ-producing T cells showed a profile with two waves separated by a long period of minimal response. Multiparametric FACS analysis showed two populations of CD3+CD8+ T cells that were specific for all HIV Ags. These cells had similar robust proliferation abilities and contained granzyme B. However, only a few produced IFN-γ. Both IFN-γ-producing and non-IFN-γ-producing HIV-specific CD8+ T cells were detected in the early stage (week (W)1 and W2 postimmunization (PI)), in the prolonged intermediate period of minimal response (W4-W26 PI), and in the final late phase of increased response (W30-W63 PI). Our longitudinal characterization showed that both subsets of cells underwent expansion, contraction, and memory generation/maintenance phases throughout the lifespan of the animal. Altogether, these findings bring insight to the heterogeneity of the immune T cell response induced by a single immunization with this DNA and strengthen the concept that used of the IFN-γ-ELISPOT assay alone may be insufficient to detect critical T cell responses to candidate HIV vaccines.

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Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8⁺T-Cell Epitopes

Cited by 217 publications

References 79 publications

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

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

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

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Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8+T-Cell Epitopes

Cited by 217 publications

References 79 publications

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

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

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

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Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8⁺T-Cell Epitopes

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