A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

Gómez, Carmen Elena; Perdiguero, Beatriz; García-Arriaza, Juan; Cepeda, Victoria; Sánchez-Sorzano, Carlos Óscar; Mothe, Beatriz; Jiménez, José Luís; Muñoz‐Fernández, María Ángeles; Gatell, José M.; Quirós, Juan Carlos López Bernaldo de; Berthou, Christian; García, Felipe; Esteban, Mariano

doi:10.1371/journal.pone.0141456

Cited by 21 publications

(31 citation statements)

References 45 publications

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“…In addition, REDUC did not include early-treated individuals with relatively intact immunity, and the detection of reduced polyfunctionality of vaccine-induced T-cells could have been limited. In BCN02, the first MVA.HIVconsv vaccination enhanced polyfunctionality, especially in CD4 + T cells, in line with previous reports showing that MVA-vectored vaccination can improve the polyfunctionality and T effector memory phenotype in CD4 + T cells more so than in CD8 + T cells (38). This increased effector function profile induced by MVA 1 was reduced upon RMD treatment but did not lead to a net reduction of the latent reservoir compared to baseline.…”

Section: Discussionsupporting

confidence: 87%

In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

et al. 2020

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Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4 + T cells from HIV-1 + individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1 + individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8 + T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure.

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Section: Discussionsupporting

confidence: 87%

In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

et al. 2020

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“…The data also showed a modest but statistically significant delay in viral rebound in the vaccinees, particularly in vaccinated individuals not receiving disulfiram (p = 0.01) [ 14 ]. Here, we show that, in contrast to the modest elevation in magnitude of immune responses seen upon vaccination and reported previously[ 14 ] [ 16 ], there was a major increase in breadth and total magnitude of HIV-1 specific T cell responses after treatment interruption. Total magnitude of HIV-1 responses increased from a median of 1,235 to 4,054 SFC/10 6 PBMC in placebos (p = 0.0078, Wilcoxon paired test) and median of 1,577 SFC/10 6 PBMC at STI start to 4,767 SFC/10 6 PBMC at 12 weeks after STI (p = 0.049, Wilcoxon paired test, Fig 1A ) in vaccinees.…”

Section: Resultscontrasting

confidence: 79%

“…Here, we tested such potential predictors of vaccine outcome in a recently completed therapeutic vaccine trial, referred to as RISVAC03. This trial was a double-blinded phase I clinical trial that assessed the safety and immunogenicity of an MVA-B candidate vaccine given alone or in combination with disulfiram in chronically infected, cART treated individuals who underwent STI post-vaccination [ 14 ][ 15 ][ 16 ]. In the present work, we sought to integrate host and vaccine-induced virological and immune parameters in order to study possible vaccine-exerted effects on rebounding virus, and to define correlates of viral rebound dynamics after STI.…”

Section: Introductionmentioning

confidence: 99%

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B

et al. 2017

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The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches.

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“…MVA-B is an immunogenic vaccine which induces a T cell response in HIV-1-infected patients (7, 8). As expected, we did not observe any significant differences in the expression of CD300 molecules in monocytes of HIV-1-infected patients before and after vaccination.…”

Section: Discussionmentioning

confidence: 99%

Monocytes Phenotype and Cytokine Production in Human Immunodeficiency Virus-1 Infected Patients Receiving a Modified Vaccinia Ankara-Based HIV-1 Vaccine: Relationship to CD300 Molecules Expression

et al. 2017

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A modified vaccinia Ankara-based HIV-1 vaccine clade B (MVA-B) has been tested for safety and immunogenicity in low-risk human immunodeficiency virus (HIV)-uninfected individuals and as a therapeutic vaccine in HIV-1-infected individuals on combined antiretroviral therapy (cART). As a therapeutic vaccine, MVA-B was safe and broadly immunogenic; however, patients still showed a viral rebound upon treatment interruption. Monocytes are an important part of the viral reservoir and several studies suggest that they are partly responsible for the chronic inflammation observed in cART-treated HIV-infected people. The CD300 family of receptors has an important role in several diseases, including viral infections. Monocytes express CD300a, c, e, and f molecules and lipopolysaccharide (LPS) and other stimuli regulate their expression. However, the expression and function of CD300 receptors on monocytes in HIV infection is still unknown. In this work, we investigated for the first time the expression of CD300 molecules and the cytokine production in response to LPS on monocytes from HIV-1-infected patients before and after vaccination with MVA-B. Our results showed that CD300 receptors expression on monocytes from HIV-1-infected patients correlates with markers of HIV infection progression and immune inflammation. Specifically, we observed a positive correlation between the expression of CD300e and CD300f receptors on monocytes with the number of CD4+ T cells of HIV-1-infected patients before vaccination. We also saw a positive correlation between the expression of the inhibitory receptor CD300f and the expression of CD163 on monocytes from HIV-1-infected individuals before and after vaccination. In addition, monocytes exhibited a higher cytokine production in response to LPS after vaccination, almost at the same levels of monocytes from healthy donors. Furthermore, we also described a correlation in the expression of CD300e and CD300f receptors with TNF-α production in response to LPS, only in monocytes of HIV-1-infected patients before vaccination. Altogether, our results describe the impact of HIV-1 and of the MVA-B vaccine in cytokine production and monocytes phenotype.

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A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

Cited by 21 publications

References 45 publications

In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B

Monocytes Phenotype and Cytokine Production in Human Immunodeficiency Virus-1 Infected Patients Receiving a Modified Vaccinia Ankara-Based HIV-1 Vaccine: Relationship to CD300 Molecules Expression

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