Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

Abstract

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.

Deletion of the Vaccinia Virus N2L Gene Encoding an Inhibitor of IRF3 Improves the Immunogenicity of Modified Vaccinia Virus Ankara Expressing HIV-1 Antigens

“…Recently, it has been demonstrated that VACV N2L encodes a nuclear inhibitor of IRF3 that blocks the IFN I signaling pathway at the intracellular level (59). As part of our effort to find out the immunomodulatory role of the VACV Bcl-2 family of proteins (30), here we deleted the VACV N2L gene from an MVA vector-based HIV/AIDS vaccine candidate termed MVA-B, which expresses HIV-1 Env, Gag, Pol, and Nef antigens from clade B (60) and has been well characterized in vitro (61,65), in mice (42,60,(62)(63)(64), in nonhuman primates (66), and in a phase I clinical trial in humans (12,14), showing that MVA-B is a promising HIV/ AIDS vaccine candidate that is safe, highly immunogenic, and able to induce broad, polyfunctional, and durable CD4 ϩ and CD8 ϩ T cell responses to HIV-1 antigens, together with humoral responses to Env.…”

“…This was done by deleting the VACV N2L gene from the vector backbone of MVA-B, an HIV/AIDS vaccine candidate based on an attenuated recombinant MVA vector expressing HIV-1 Env and Gag-Pol-Nef (GPN) antigens from clade B (60). MVA-B has been extensively studied in vitro and in different animal models (42,(60)(61)(62)(63)(64)(65)(66), where it triggers strong and durable immune responses to HIV-1 antigens. Furthermore, MVA-B was safe and highly immunogenic when tested in a phase I clinical trial with healthy human volunteers, inducing humoral responses to Env and HIV-1-specific CD4 ϩ and CD8 ϩ T cell responses that were high, broad, polyfunctional, and long-lasting (12,14).…”

Dendritic cell based vaccines for HIV infection

“…MD-DCs pulsed with recombinant virus has been tested in vitro 58 and in clinical trials. 48 We have reported that MVA-B (MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B) infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8 + T-cell response including proliferation, secretion of IFNgamma, IL-2, TNF-α, MIP-1beta, MIP1alpha, RANTES, and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4 + T lymphocytes.…”

Therapeutic vaccination to treat chronic infectious diseases

“…25 This study and others strongly suggest that cross-presentation is likely the primary mechanism of action responsible for the immunogenicity achieved following MVA vaccination. 26,27 Furthermore, MVA is known to trigger early migration of leukocytes at the site of infection. 28 DCs are expected to be recruited at the inoculation site, to sample MVA-infected dying cells (e.g., fibroblasts and adipocytes) and following maturation to migrate to lymph nodes and activate antigen-specific T cells.…”