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Interactome of the HIV-1 proteome and human host RNA

ABSTRACT: The human immunodeficiency virus (HIV-1) is highly dependent on a variety of host factors. Beside proteins, host RNA molecules have been reported to aid HIV-1 replication and latency maintenance. Here we report the use of multiple workflows of native RNA immunoprecipitation and sequencing (nRIPseq) to determine direct host RNA interaction partners of all 18 HIV-1 (poly)proteins. We identified 1,727 HIV-1 protein – human RNA interactions in the Jurkat cell line and 1,558 interactions in SupT1 cells for a subset of proteins. We discovered different cellular pathways that seem to be used or controlled by HIV-1 on the RNA level: Tat binds for example mRNAs of proteins involved in the super elongation complex (AFF1-4, Cyclin-T1). Correlation of the interaction scores (based on binding abundancy) allowed to identify the highest confidence interactions, for which we performed a small-scale knockdown screen that led to the identification of three HIV-1 protein binding RNA interactors involved in HIV-1 replication (AFF2, H4C9 and RPLP0).

ORGANISM(S): Homo sapiens

PROVIDER: GSE268788 | GEO | 2024/07/31

REPOSITORIES: GEO

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Project description:During HIV-1 infection, there is a massive perturbation of host gene expression, but as yet, genome-wide studies have not identified host genes affecting HIV-1 replication in lymphatic tissue, the primary site of virus-host interactions. In this study, we isolated RNA from the inguinal lymph nodes of 22 HIV-1-infected individuals and utilized a microarray approach to identify host genes critically important for viral replication in lymphatic tissue by examining gene expression associated with viral load. Strikingly, ~95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset (1) inhibit cellular activation/proliferation (ex.: TCFL5, SOCS5 and SCOS7, KLF10), (2) promote heterochromatin formation (ex.: HIC2, CREBZF, ZNF148/ZBP-89), (3) increase collagen synthesis (ex.: PLOD2, POSTN, CRTAP), and (4) reduce cellular transcription and translation. Potential anti-HIV-1 restriction factors were also identified (ex.: NR3C1, HNRNPU, PACT). Only ~5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all these genes function in innate and adaptive immunity, particularly highlighting a heightened interferon system. The predominance of negative correlations as well as the disconnect between host defenses and viral load point to the importance of genes that regulate target cell activation and genes that code for potentially new restriction factors as determinants of viral load rather than conventional host defenses. Total RNA was isolated from the inguinal lymph nodes of 22 HIV-1-infected subjects at different clinical stages (and varying viral loads) and prepared for RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 microarrays. Replicate arrays were performed for lymph node samples to minimize assay noise and host genes critically important for viral replication in lymphatic tissue were identified by examining gene expression and its association with viral load. Replicates were not performed for samples WB91 and TS35 due to limited amounts of biomaterial.

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Interactome of the HIV-1 proteome and human host RNA

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