Abstract
It remains poorly defined whether any human miRNAs play protective roles during HIV infection. Here, focusing on a unique cohort of HIV-infected former blood donors, we identified miR-31 (hsa-miR-31) by comparative miRNA profiling as the only miRNA inversely correlating with disease progression. We further validated this association in two prospective cohort studies. Despite conservation during evolution, hsa-miR-31, unlike its mouse counterpart (mmu-miR-31), was downregulated in human T cell upon activation. Our ex vivo studies showed that inhibiting miR-31 in naïve CD4+ T cells promoted a transcriptional profile with activation signature. Consistent with this skewing effect, miR-31 inhibition led to remarkably increased susceptibility to HIV infection. The suppressive nature of miR-31 in CD4+ T cell activation was pinpointed to its ability to decrease T-bet, the key molecule governing IFN-γ production and activation of CD4+ T cells, by directly targeting the upstream STAT1 transcriptional factor for downregulation, thus blunting Th1 response. Our results implicated miR-31 as a useful biomarker for tracking HIV disease progression and, by demonstrating its importance in tuning the activation of CD4+ T cells, suggested that miR-31 may play critical roles in other physiological contexts where the CD4+ T cell homeostasis needs to be deliberately controlled.
Highlights
HIV-1/AIDS has become a major infectious disease posing severe threats to human life and global economy
To gain insight into the roles of miRNAs during HIV-1 infection, we compared the miRNA profiles of whole blood samples from a cohort of HIV-infected former blood donors (FBDs), who donated plasma during 1995-1996 in Yuncheng city, China and contracted HIV-1 infection from common-source of contaminated blood [27, 28]
The blood samples were collected during one follow-up visit in November 2010
Summary
HIV-1/AIDS has become a major infectious disease posing severe threats to human life and global economy. According to UNAIDS, the cumulative number of patients acquiring HIV/AIDS is estimated to be 77.5 million, half of whom were still alive at the end of 2020 [1]. With differentiated CD4+ T cells as its primary target, HIV infection progressively deteriorated human immune system through three major phases: primary, chronic, and AIDS. The ensuing chronic phase is contrastingly marked by a decrease in viral replication alongside a generalized activation of immune system, a period that last miR-31 Governs T-Cell Homeostasis variably with an average of 8-10 years [2]. AIDS represents the final stage of HIV disease when patients display clinical manifestations including low CD4+ T cell counts and compromised cellular immunity that renders increased susceptibility to infection and tumor formation [3]
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