Upregulation of PTPRC and Interferon Response Pathways in HIV-1 Seroconverters Prior to Infection

Abstract

Human immunodeficiency virus 1 (HIV-1) exposed seronegative (HESN) individuals may have unique characteristics that alter susceptibility to HIV-1 infection. However, identifying truly exposed HESN is challenging. We utilized stored data and biospecimens from HIV-1 serodifferent couple cohorts, in which couples' HIV-1 exposures were quantified based on unprotected sex frequency and viral load of the partner with HIV-1. We compared peripheral blood gene expression between 15 HESN and 18 seroconverters prior to infection. We found PTPRC (encoding CD45 antigen) and interferon-response pathways had significantly higher expression among individuals who went on to become seropositive and thus may be a signature for increased acquisition risk.

Keywords: HIV-1; acquisition; gene expression; host resistance; microarray.

Figure 1.

Differential gene expression analysis reveals unique biomarkers of seroconverter status. A, Volcano plot indicating the log₂ fold-changes and P values for all tested probes. The top 5 signals with greater fold changes and small P values are annotated with the human gene names in italics. B, Boxplot (Bold line-median, box-interquartile range, top and bottom hortizontal lines-maximum and minimum values excluding outliers) with bee swarm plot superimposed for PTPRC gene expression between HIV-1 seroconverter and HIV-1 exposed seronegative (HESN) participants. Higher expression of PTPRC gene is observed in seroconverter compared to HESN. C, Heatmap containing the differentially expressed genes with an absolute log₂ fold-change >0.5 and adjusted P value less than 0.05 under false discovery rate correction.

Figure 2.

Gene set enrichment analysis-based pathway analysis of seroconverter differentially expressed genes. A, Bar plot indicating the normalized enrichment score of significant Hallmark pathways with adjusted P values less than .05. Positive values indicate an enrichment in seroconverters, and negative value indicate enrichment in seronegative participants. Several immune or inflammation-related pathways are identified with high scores, including interferon responses and JAK-STAT signaling. B, Heatmap containing leading edges of the interferon-α and -γ pathways with adjusted P value (in differential gene expression analysis) less than .25. Cell color represents the gene expression level—higher expression in red and lower expression in blue. Samples are annotated with HIV infection status, with green indicating HESNs and orange indicating seroconverters. Genes are annotated with adjusted P values and log₂ fold-changes from differential gene expression analysis and whether they are included in the gene sets. Seroconverters show a higher expression of leading-edge genes in interferon response pathways.