Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Abstract

NK cells during chronic viral infection have been well studied in the past. We performed an unbiased next-generation RNA-sequencing approach to identify commonalities or differences of the effect of HIV, HCV and HBV viremia on NK cell transcriptomes. Using cell sorting, we obtained CD3-CD56+ NK cells from blood of 6 HIV, 8 HCV, and 32 HBV infected patients without treatment. After library preparation and sequencing, we used an in-house analytic pipeline to compare expression levels with matched healthy controls. In NK cells from HIV, HCV and HBV patients, transcriptome analysis identified 272, 53, and 56 differentially expressed genes, respectively (fold change >1.5, q-value 0.2). Interferon stimulated genes were induced in NK cells from HIV/HCV patients, but not during HBV infection. HIV viremia downregulated ribosome assembly genes in NK cells. In HBV, viral load and ALT variation had little effect on genes related to NK effector function. In conclusion, we compare, for the first time, NK cell transcripts of viremic HIV, HCV and HBV patients. We clearly demonstrate distinctive NK cell gene signatures in 3 different populations, suggestive for a different degree of functional alterations of the NK cell compartment as compared to healthy individuals. Three viruses exist that can result in persistently high viral loads in immune competent humans: HIV, hepatitis C and hepatitis B. In the last decades, using flow cytometry and in vitro assays on NK cells from patients with these diseases, several impairments have been established, particularly during and possibly contributing to HIV viremia. However, the background of NK cell impairments in viremic patients is not well understood. In this study we describe the NK cell transcriptome of patients with high viral loads of different etiologies. We clearly demonstrate distinctive NK cell gene signatures, with regard to ISG induction, expression of genes coding for activation markers or proteins involved in cytotoxic action, as well immunological genes. This study provides important details necessary to uncover the origin of functional and phenotypical differences between viremic patients and healthy subjects, and provides many leads that can be confirmed using future in vitro manipulation experiments.

An integrative genomic analysis of transcriptional profiles identifies characteristic genes and patterns in HIV-infected long-term non-progressors and elite controllers

“…This indicates that defects in ribosome components and blockade of translational initiation probably play a significant deleterious role in HIV progression. In agreement with our findings, a recent study reported several ribosomal formation genes including RPL27, PRS7, RPL24, RPS13 and RPL10L was down regulated in NK cells from HIV infected individuals [56]. Our most interesting findings were the identification of gene networks which were highly associated with nonprogression status in VNPs.…”

A single-cell atlas of the peripheral immune response to severe COVID-19

“…3f, g ). IFNs promote the activation of antiviral responses in NK cells 36 , and ISGs are upregulated in NK cells in multiple settings of acute viral infection 37 . What differentiates the activation of IFN-mediated pathways in NK cells during SARS-CoV-2 infection, and how this relates to clinical outcomes and the generation of antiviral immunity, remains to be elucidated.…”

Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

“…We report here that the functional impairment imposed by CHB significantly imprints the NK cell transcriptome. A recent study was performed on HBV-infected patients from all four phases of infection ( Boeijen et al, 2019 ). Very few transcripts were significantly deregulated in the inactive carriers compared to HD controls.…”