Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals

Julianna Lisziewicz, Nyasha Bakare, Sandra A Calarota, Dénes Bánhegyi, János Szlávik, Eszter Ujhelyi, Enikő R Tőke, Levente Molnár, Zsolt Lisziewicz, Brigitte Autran, Franco Lori, Julianna Lisziewicz, Nyasha Bakare, Sandra A Calarota, Dénes Bánhegyi, János Szlávik, Eszter Ujhelyi, Enikő R Tőke, Levente Molnár, Zsolt Lisziewicz, Brigitte Autran, Franco Lori

Abstract

Background: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART).

Methodology/principal findings: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline.

Conclusions/significance: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up.

Trial registration: ClinicalTrial.gov NCT00712530.

Conflict of interest statement

Competing Interests: Study sponsored by Commercial funder Genetic Immunity, LLC; JL, NB, ZL and FL are employees of or hold shares in Genetic Immunity Inc. There are several patent applications to protect DermaVir product and technology - JL, FL, ET from Genetic Immunity could benefit. DermaVir is a immunotherapeutic product candidate in development by Genetic Immunity. There are no other patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. DermaVir immunization.
Figure 1. DermaVir immunization.
(a) DermaVir administration area on the skin surface under 80 cm2 large DermaPrep patches. The immunization starts with a standardized skin preparation to interrupt the stratum corneum and activate Langerhans cells causing a mild and transient erythema. (b) Cross-sectional view of the epidermis with approximately 8 million Langerhans cells estimated under one patch. (c) DermaVir pathogen-like nanomedicine, a formulation to facilitate cellular entry, nuclear transport and expression of the plasmid DNA-encoded antigens. The nanomedicine consists of the “core” that is a condensed plasmid DNA and a mannosylated polyethylenimine “envelope” , . (d) Needle-free, topical, Langerhans cell-targeting vaccine administration with the DermaPrep device. The special semi-occlusive patch is kept on the skin for three hours. (e) Activated epidermal Langerhans cells take up DermaVir, mature to antigen presenting dendritic cells and migrate to the draining lymph nodes. (f) In the lymph node dendritic cells express the DNA-encoded antigens: 15 HIV proteins that assemble into a complex VLP+ . These cells present several hundreds of epitopes to naïve T cells and prime HIV-specific precursor/memory T cells. (g) HIV-specific precursor/memory T cells with high proliferative capacity circulate in the body to kill HIV-infected cells.
Figure 2. Kinetics of the HIV-specific PHPC…
Figure 2. Kinetics of the HIV-specific PHPC responses.
Long-lived HIV-specific precursor/memory T cells with high proliferative capacity prior and after a single DermaVir immunization in each HIV-infected individual on fully suppressive cART. 1st raw: Low dose; 2nd raw: Medium Dose; 3rd raw: high dose DermaVir immunizations. Frequency of PHPC responses against Tat, Rev and the three Gag antigens are shown prior (Day 0) and after DermaVir immunization (day 7, day 14, day 28, and week 48). Every sample was assayed in duplicate or triplicate, and data are shown as PHPC counts/106 PBMC.

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