Transcriptome Analysis Identifies Altered Biological Processes and Novel Markers in Human Immunodeficiency Virus-1 Long-Term Non-Progressors

Abstract

Background: The latent reservoir of Human Immunodificiency Virus-1 (HIV-1) has been a major barrier to the complete eradication of HIV-1 and the development of HIV therapy. Longterm non-progressors (LTNPs) are a rare group of patients with HIV-1 who can spontaneously control HIV-1 replication without antiretroviral therapy. Transcriptome analysis is necessary to predict the pathways involved in the natural control of HIV-1, elucidate the mechanisms involved in LTNPs, and find biomarkers for HIV-1 reservoir therapy. Materials and Methods: In this study, we obtained peripheral blood mononuclear cells from two LTNP subjects at multiple time points and performed RNA-sequencing analyses. Results: We found that LTNPs and normal subjects had different transcriptome profiles. Functional annotation analysis identified that differentially expressed genes in LTNPs were enriched in several biological pathways such as cell cycle-related pathways and the transforming growth factor-beta signaling pathway. However, genes that were downregulated in LTNPs were associated with immune responses such as the interferon response and IL2- STAT5 signaling. Protein-protein interaction network analysis showed that CD8A, KLRD1, ASGR1, and MLKL, whose gene expression was upregulated in LTNPs, directly interacted with HIV-1 proteins. The network analysis also found that viral proteins potentially regulated host genes that were associated with immune system processes, metabolic processes, and gene expression regulation. Conclusion: Our longitudinal transcriptome analysis of the LTNPs identified multiple previously undescribed pathways and genes that may be useful in the discovery of novel therapeutic targets and biomarkers. Keywords: Human immunodeficiency virus; HIV-1 non-progressors