Induction of Broad and Polyfunctional HIV-1-Specific T Cell Responses by the Multiepitopic Protein TMEP-B Vectored by MVA Virus.

Beatriz Perdiguero,Carlos Oscar S Sorzano,Carmen Elena Gómez,Lidia Saiz,Pilar Mediavilla,Mariano Esteban,Cristina Sánchez-Corzo

doi:10.3390/vaccines7030057

Beatriz Perdiguero, Carlos Oscar S Sorzano + Show 5 more

Open Access

https://doi.org/10.3390/vaccines7030057

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Abstract

A human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) vaccine able to induce long-lasting immunity remains a major challenge. We previously designed a T cell multiepitopic immunogen including protective conserved epitopes from HIV-1 Gag, Pol and Nef proteins (TMEP-B), that induced potent HIV-1-specific CD8 T cells when vectored by DNA and combined with the vaccine candidate modified vaccinia virus Ankara (MVA)-B. Here, we described the vectorization of TMEP-B in MVA (MVA-TMEP) and evaluated the T cell immunogenicity profile elicited in mice when administered in homologous (MVA/MVA) or heterologous (DNA/MVA) prime/boost vector regimens or using homologous or heterologous inserts. The heterologous vector regimen was superior to the homologous protocol in inducing T cell responses. DNA-TMEP-primed animals boosted with MVA-TMEP or MVA-B exhibited the highest magnitudes of HIV-1-specific CD8, CD4 and T follicular helper (Tfh) cells, with MVA-TMEP significantly expanding Gag-specific CD8 T cell responses. In the homologous vector regimen, all groups exhibited similar HIV-1-specific CD8 and CD4 T cell responses, but both MVA-B/MVA-B and MVA-TMEP/MVA-TMEP combinations elicited higher Gag-Pol-Nef (GPN)-specific CD8 T cell responses compared to MVA-TMEP/MVA-B. Our results revealed an enhanced induction of HIV-1-specific T cell responses by TMEP-B when vectored in both DNA and MVA, and supported their use in combined prime/boost strategies for HIV-1 prevention and/or therapy.

Highlights

Since the discovery of human immunodeficiency virus (HIV) more than 30 years ago as the causative agent of acquired immune deficiency syndrome (AIDS), the virus has spread worldwide to pandemic proportions
In an effort to further improve the HIV-1 specific T cell responses to conserved HIV-1 regions in a prime/boost protocol, here we describe the vectorization of TMEP-B in modified vaccinia virus Ankara (MVA) vector to generate the MVA-TMEP recombinant virus, and evaluate the T cell immunogenicity profile elicited in mice when administered both in homologous (MVA/MVA) or heterologous (DNA/MVA) prime/boost protocols or using homologous or heterologous inserts
A growth curve analysis was performed in primary chicken embryo fibroblast (CEF) cells to determine whether the insertion of TMEP-B gene affected the viral growth of MVA-TMEP in cell culture

Summary

Introduction

Since the discovery of human immunodeficiency virus (HIV) more than 30 years ago as the causative agent of acquired immune deficiency syndrome (AIDS), the virus has spread worldwide to pandemic proportions. AIDS-related deaths (51% since the peak in 2004), the development of an effective vaccine remains to be a priority in the field (http://www.unaids.org). Natural immunity and vaccine immune correlates of protection against HIV are not well defined yet, but there is an agreement that an ideal candidate should be able to mobilize both cellular and humoral immune responses. The challenge for such vaccine development is that viral antigens, delivery. The current ongoing preclinical and clinical trials combining different antibody- and T cell-inducing vaccine candidates using homologous or heterologous prime-boost strategies is the most realistic option to overcome the above challenge and confer enhanced protection against HIV infection [1,2]

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