Figure (top) showing the protein–protein interaction network that links between CD8+ T-cell response-associated genes and constituents of functional gene modules differentially regulated by MRKAd5/HIV. Study is done by Zak DE et al., PNAS, 2012.
The Step Study revealed that the MRKAd5/HIV had poor efficacy in protecting against HIV-1 infection, especially in subjects with pre-existing Ad5 immunity. However, no clear mechanisms have been identified to date why the seropositive subjects showed reduced efficacy. In this manuscript, Zak DE et al., describe the possible mechanisms of vaccine failure using a systems biology approach
35 healthy HIV-1-uninfected adults, 20–50 years old were recruited for the study. 10 subjects (3 seropositive and 7 seronegative subjects) PBMCs were isolated and transcript levels were analysed by microarray at 4–6, 24, 72, and 168 h post-vaccination.
Strong induction of innate immune responses were detected at the gene and protein level, peaking at 24 hours post-vaccination and resolving at 72 hours post-vaccination. In addition, protein levels of CXCL-10, ITAC, monocyte chemoattractant protein-1 (MCP-1), and MCP-2, as well as immunoregulatory IL-10 and IL-1Ra, were upregulated.
92% concordance between the in vivo and in vitro induction of IFN response genes was observed, indicating that these immune responses observed were modulated by viral infection. Genes not captured in vitro are related to cell lineages, possibly due to lack of cell trafficking in vitro.
When comparing subjects with Ad5 nAb titers ≤ 200 and >200, significant attenuation of the innate immune responses were seen in seropositive subjects compared to the seronegative subjects.
Two chemokines, MCP-1 and MCP-2, discriminated between the strong and moderate CD8-responders as compared to those subjects with poor or no CD8 responses.
Interestingly, the gene signatures that correlated with CD8 T-cell responses were seen at day 3, where members of the “Cytotoxicity,” “T cells,” and “Lymphoid lineage” modules were positively correlated (see above figure). This finding may support the notion that prolonged upregulation of the innate immune gene transcripts could influence CD8 responses.
Data is deposited in the Gene Expression Omnibus (GEO) database, GSE22822.