Abstract
While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays.
Highlights
The development of an effective HIV vaccine has proven to be a significant challenge and the exact nature of a protective immune profile remains elusive
We demonstrate that a SIV DNA vaccine can induce strong cellular immunity and suppress SIV viral replication when administered in conjunction with a plasmid molecular adjuvant expressing RANTES
Summary of comprehensive MHC class I genotypes of Chinese-origin rhesus macaques as determined by Sanger-based and Roche/454 pyrosequence-based typing
Summary
The development of an effective HIV vaccine has proven to be a significant challenge and the exact nature of a protective immune profile remains elusive. Binding Abs were observed in most vaccinated subjects suggesting their importance in protection from infection [1]. The Ab response alone is not likely the only contributor to efficacy and a number of studies have indicated that a cellular immunity contributes to protection against HIV infection in humans and SIV infection in RMs [2,3]; high CD4+ T-cell and CD8+ T-cell gamma interferon (IFN- c) responses are associated with better viral control during chronic SIV infection [4]. In vivo depletion of CD8+ T-cells in SIV- or SHIV89.6p-infected RMs implicates the importance of T-cells in the control of viral replication during both acute [13] and chronic [14] infection. One of the goals of the current study was to develop an SIV DNA vaccine that induces strong SIV-specific cellular immune responses by optimizing its delivery using in vivo electroporation (EP) and its expression using co-delivery of a plasmid molecular adjuvant encoding the chemokine ligand 5 (RANTES)
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