Abstract
Development of a safe and efficacious vaccine against the HIV/AIDS pandemic remains a major scientific goal. We previously described an HIV/AIDS vaccine based on the modified vaccinia virus Ankara (MVA) expressing HIV-1 gp120 and Gag-Pol-Nef (GPN) of clade B (termed MVA-B), which showed moderate immunogenicity in phase I prophylactic and therapeutic clinical trials. Here, to improve the immunogenicity of MVA-B, we generated a novel recombinant virus, MVA-B ΔA40R, by deleting in the MVA-B genome the vaccinia virus (VACV) A40R gene, which encodes a protein with unknown immune function. The innate immune responses triggered by MVA-B ΔA40R in infected human macrophages, in comparison to parental MVA-B, revealed an increase in the mRNA expression levels of interferon (IFN)-β, IFN-induced genes, and chemokines. Compared to priming with DNA-B (a mixture of DNA-gp120 plus DNA-GPN) and boosting with MVA-B, mice immunized with a DNA-B/MVA-B ΔA40R regimen induced higher magnitude of adaptive and memory HIV-1-specific CD4+ and CD8+ T-cell immune responses that were highly polyfunctional, mainly directed against Env. and of an effector memory phenotype, together with enhanced levels of antibodies against HIV-1 gp120. Reintroduction of the A40R gene into the MVA-B ΔA40R genome (virus termed MVA-B ΔA40R-rev) promoted in infected cells high mRNA and protein A40 levels, with A40 protein localized in the cell membrane. MVA-B ΔA40R-rev significantly reduced mRNA levels of IFN-β and of several other innate immune-related genes in infected human macrophages. In immunized mice, MVA-B ΔA40R-rev reduced the magnitude of the HIV-1-specific CD4+ and CD8+ T cell responses compared to MVA-B ΔA40R. These results revealed an immunosuppressive role of the A40 protein, findings relevant for the optimization of poxvirus vectors as vaccines.
Highlights
The acquired immune deficiency syndrome (AIDS) pandemic caused by the human immunodeficiency virus (HIV)-1 is spreading worldwide, with high impact and severity in human health
To determine whether the modified vaccinia virus Ankara (MVA) A40R gene might have an immunomodulatory role that, in turn, could influence the immunogenicity profile of antigens delivered from a poxvirus vector, we deleted the MVA A40R gene from the HIV/AIDS vaccine candidate MVA-B [16], generating the MVA-B deletion mutant termed MVA-B ∆A40R
The results showed that, compared to parental MVA-B, MVA-B ∆A40R significantly enhanced the expression of several genes involved in the type I IFN signaling pathway, such as IFN-β, interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), and IFIT2, as well as the viral dsRNA sensor melanoma differentiation-associated protein 5 (MDA-5), and the pro-inflammatory chemokine MIP-1α, suggesting that MVA A40 protein could have an immunomodulatory role, blocking innate immune responses during virus infection
Summary
The acquired immune deficiency syndrome (AIDS) pandemic caused by the human immunodeficiency virus (HIV)-1 is spreading worldwide, with high impact and severity in human health. An effective vaccine against HIV/AIDS should stimulate both humoral and cellular immune responses to multiple HIV-1 viral antigens, including structural and regulatory proteins, and induce strong, broad, polyfunctional, and durable T- and B-cell responses [1]. Neutralizing antibodies against gp120 are crucial, due to the difficulty in obtaining immunogens capable of inducing high titers of neutralizing antibodies with broad specificities, a focus on HIV-1-specific T-cell immune responses has been one of the main routes pursued in the development of HIV-1 vaccines [2]. In non-human primates, there is a good correlation between vaccine-induced HIV-1-specific cellular immunogenicity and protection after a challenge with a pathogenic simian/human immunodeficiency virus (SHIV) [3,4,5], where CD8+ T cells play an important role in immunity to HIV-1 [5]. Of the numerous clinical trials carried out so far with different
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