Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice

Norton, Thomas; Zhen, Anjie; Tada, Takuya; Kim, Jennifer; Kitchen, Scott G.; Landau, Nathaniel R.

doi:10.1016/j.ymthe.2019.03.008

Cited by 28 publications

(38 citation statements)

References 80 publications

(96 reference statements)

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“…One of the restriction factors mediating this resistance is SAMHD1 (19,20), which depletes the cytoplasmic pool of deoxynucleoside triphosphates, affecting the reverse transcription process (21). Vpx protein from simian immunodeficiency viruses directs proteasome-mediated degradation of SAMHD1 (22), restoring HIV-1 infection in myeloid cells (19,20,23,24). Therefore, we exploited this natural inhibitor of SAMHD1, treating the monocytes with Vpx-containing viral like particles for 6 h before bdLV transduction (25,26), and reached up to 98% of transduced monocyte-derived DC.…”

Section: Introductionmentioning

confidence: 99%

Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer

et al. 2020

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The prominent role of dendritic cells (DC) in promoting tolerance and the development of methods to generate clinical grade products allowed the clinical application of tolerogenic DC (tolDC)-based therapies for controlling unwanted immune responses. We established an efficient method to generate tolerogenic human DC, producing supra-physiological levels of IL-10, by genetically engineering monocyte-derived DC with a bidirectional Lentiviral Vector (bdLV) encoding for IL-10 and a marker gene. DC IL−10 are mature DC, modulate T cell responses, promote T regulatory cells, and are phenotypically and functionally stable upon stimulation. Adoptive transfer of human DC IL−10 in a humanized mouse model dampens allogeneic T cell recall responses, while murine DC IL−10 delays acute graft-vs.-host disease in mice. Our report outlines an efficient method to transduce human myeloid cells with large-size LV and shows that stable over-expression of IL-10 generates an effective cell product for future clinical applications in the contest of allogeneic transplantation.

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Section: Introductionmentioning

confidence: 99%

Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer

et al. 2020

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“…An interesting approach for COVID-19 vaccine development comprise the application of lentivirus transduced dendritic cells (DCs). It has previously been demonstrated that immunization of mice with DCs transduced with lentivirus vectors expressing CD40L and the HIV-1 SL9 epitope induced enhanced antigen-specific T cell proliferation and memory differentiation [ 133 ]. In this context, a Phase I trial applying DCs transduced with a lentivirus vector expressing the SARS-CoV-2 S protein (LV-SMENP) has been initiated in China [ 127 ].…”

Section: Clinical Trialsmentioning

confidence: 99%

Coronavirus Pandemic: Treatment and Future Prevention

Lundström¹

2020

Future Microbiol.

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The rapid spread of SARS-CoV-2 leading to the COVID-19 pandemic with more than 400,000 deaths worldwide and the global economy shut down has substantially accelerated the research and development of novel and efficient COVID-19 antiviral drugs and vaccines. In the short term, antiviral and other drugs have been subjected to repurposing against COVID-19 demonstrating some success, but some excessively hasty conclusions drawn from significantly suboptimal clinical evaluations have provided false hope. On the other hand, more than 300 potential therapies and at least 150 vaccine studies are in progress at various stages of preclinical or clinical research. The aim here is to provide a timely update of the development, which, due to the intense activities, moves forward with unprecedented speed.

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“…Previous studies on hu-mice and in line with NHP studies showed that blocking the PD-1/PD-L1 axis with a blocking anti-PD-1 can reduce viral load by half [ 80 ], while anti-PDL1 improves CD4+ T cell levels [ 81 ]. Interestingly, a very recent study has evaluated in hu-mice a lentiviral vector-based Dendritic cell (DC) vaccine, in which HIV-1 antigen was co-expressed with CD40 ligand (CD40L) and a soluble high-affinity PD-1 dimer [ 82 ]. The idea was to improve the ex vivo DC-based vaccines already tested in HIV-infected patients with rather little success [ 83 , 84 , 85 ] by providing long-term endogenous antigen presentation, enhancing the maturation of DC through the activation of CD40, and inhibiting the PD-1/PD-L1 axis.…”

Section: Humanized-mice (Hu-mice) For Combinatorial Therapy Testinmentioning

confidence: 99%

“…The idea was to improve the ex vivo DC-based vaccines already tested in HIV-infected patients with rather little success [ 83 , 84 , 85 ] by providing long-term endogenous antigen presentation, enhancing the maturation of DC through the activation of CD40, and inhibiting the PD-1/PD-L1 axis. In this proof-of-concept study, the vaccination of hu-mice with genetically modified DC induced an anti-HIV-1 immune response that suppressed viral loads as early as 2 weeks post-HIV-1 challenge and increased the function of the responding T cells [ 82 ].…”

Section: Humanized-mice (Hu-mice) For Combinatorial Therapy Testinmentioning

confidence: 99%

The Potential of Immune Modulation in Therapeutic HIV-1 Vaccination

et al. 2020

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We discuss here some of the key immunological elements that are at the crossroads and need to be combined to develop a potent therapeutic HIV-1 vaccine. Therapeutic vaccines have been commonly used to enhance and/or recall pre-existing HIV-1-specific cell-mediated immune responses aiming to suppress virus replication. The current success of immune checkpoint blockers in cancer therapy renders them very attractive to use in HIV-1 infected individuals with the objective to preserve the function of HIV-1-specific T cells from exhaustion and presumably target the persistent cellular reservoir. The major latest advances in our understanding of the mechanisms responsible for virus reactivation during therapy-suppressed individuals provide the scientific basis for future combinatorial therapeutic vaccine development.

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Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice

Cited by 28 publications

References 80 publications

Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer

Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer

Coronavirus Pandemic: Treatment and Future Prevention

The Potential of Immune Modulation in Therapeutic HIV-1 Vaccination

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