Gene dysregulation in acute HIV-1 infection - early transcriptomic analysis reveals the crucial biological functions affected
Parker, Erica (University of Western Australia)
Judge, Melinda A. (University of Western Australia)
Pastor Palomo, Lucía (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Fuente-Soro, Laura (Hospital Clínic i Provincial de Barcelona)
Jairoce, Chenjerai (Centro de Investigação em Saúde da Manhiça (CISM))
Carter, Kim W. (Telethon Kids Institute)
Anderson, Denise (Telethon Kids Institute)
Mandomando, Inacio (Centro de Investigação em Saúde da Manhiça (CISM))
Clifford, Holly D. (Telethon Kids Institute)
Naniche, Denise (Hospital Clínic i Provincial de Barcelona)
Le Souëf, Peter Neils (Telethon Kids Institute)
Universitat Autònoma de Barcelona

Fecha:	2023
Resumen:	Transcriptomic analyses from early human immunodeficiency virus (HIV) infection have the potential to reveal how HIV causes widespread and lasting damage to biological functions, especially in the immune system. Previous studies have been limited by difficulties in obtaining early specimens. A hospital symptom-based screening approach was applied in a rural Mozambican setting to enrol patients with suspected acute HIV infection (Fiebig stage I-IV). Blood samples were collected from all those recruited, so that acute cases and contemporaneously recruited, uninfected controls were included. PBMC were isolated and sequenced using RNA-seq. Sample cellular composition was estimated from gene expression data. Differential gene expression analysis was completed, and correlations were determined between viral load and differential gene expression. Biological implications were examined using Cytoscape, gene set enrichment analysis, and enrichment mapping. Twenty-nine HIV infected subjects one month from presentation and 46 uninfected controls were included in this study. Subjects with acute HIV infection demonstrated profound gene dysregulation, with 6131 (almost 13% of the genome mapped in this study) significantly differentially expressed. Viral load was correlated with 1. 6% of dysregulated genes, in particular, highly upregulated genes involved in key cell cycle functions, were correlated with viremia. The most profoundly upregulated biological functions related to cell cycle regulation, in particular, CDCA7 may drive aberrant cell division, promoted by overexpressed E2F family proteins. Also upregulated were DNA repair and replication, microtubule and spindle organization, and immune activation and response. The interferome of acute HIV was characterized by broad activation of interferon-stimulated genes with antiviral functions, most notably IFI27 and OTOF. BCL2 downregulation alongside upregulation of several apoptotic trigger genes and downstream effectors may contribute to cycle arrest and apoptosis. Transmembrane protein 155 (TMEM155) was consistently highly overexpressed during acute infection, with roles hitherto unknown. Our study contributes to a better understanding of the mechanisms of early HIV-induced immune damage. These findings have the potential to lead to new earlier interventions that improve outcomes.
Ayudas:	Ministerio de Ciencia e Innovación SAF-2011-27901 Ministerio de Economía y Competitividad FI12/00096
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Acute HIV infection ; Gene expression profiling ; HIV ; Host microbial interactions ; Innate immunity ; Mozambique ; Sub-Sahara Africa (SSA)
Publicado en:	Frontiers in cellular and infection microbiology, Vol. 13 (april 2023) , ISSN 2235-2988

DOI: 10.3389/fcimb.2023.1074847
PMID: 37077524

17 p, 9.6 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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