HIV-1 Hijacks HGF/c-MET Signaling to Promote Viral Entry and Replication in Primary CD4+ T Cells

Shraddha Tripathi; Madeleine M. Allen; Li Wu

doi:10.64898/2026.08.03.742552

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HIV-1 Hijacks HGF/c-MET Signaling to Promote Viral Entry and Replication in Primary CD4+ T Cells

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HIV-1 Hijacks HGF/c-MET Signaling to Promote Viral Entry and Replication in Primary CD4+ T Cells

Shraddha Tripathi, Madeleine M. Allen and Li Wu

bioRxiv

Cold Spring Harbor Laboratory, 1.1

08/04/2026

DOI: 10.64898/2026.08.03.742552

PMCID: PMC13484655

PMID: 42620025

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https://doi.org/10.64898/2026.08.03.742552View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The mesenchymal-epithelial transition factor (c-MET) is a receptor tyrosine kinase best known for mediating hepatocyte growth factor (HGF) signaling in cancer, yet its role in HIV-1 infection remains undefined. Here we identify c-MET as a host factor that facilitates HIV-1 replication in CD4+ T cells by promoting viral entry. HIV-1 infection upregulates c-MET transcripts and phosphorylation in primary CD4+ T cells. Knockout or pharmacological inhibition of c-MET in CD4+ T cells significantly reduces HIV-1 Gag expression, viral production, and infectivity. Mechanistically, c-MET disruption reduces cell-surface expression of the HIV-1 receptor CD4 and the coreceptor CXCR4, thereby restricting viral entry and infection. Furthermore, c-MET disruption diminishes activation of NF-κB, STAT1/3, and MAPK signaling pathways that are critical for HIV-1 gene expression. These findings reveal that HIV-1 exploits HGF/c-MET signaling to coordinate entry receptor availability and intracellular signaling, uncovering a previously unrecognized host pathway that supports viral replication in CD4+ T cells. Overall, our results highlight an essential role for HGF/c-MET signaling in HIV-1 infection of primary CD4+ T cells and suggest a potential host-directed therapeutic target. c-MET facilitates HIV-1 replication in CD4+ T cells by promoting viral entry HIV-1 infection upregulates c-MET transcripts and phosphorylation in CD4+ T cells c-MET disruption reduces CD4 and CXCR4 expression on CD4+ T cell surfaces c-MET disruption diminishes activation of cellular pathways important for HIV-1

Microbiology

Details

Title: Subtitle: HIV-1 Hijacks HGF/c-MET Signaling to Promote Viral Entry and Replication in Primary CD4+ T Cells
Creators: Shraddha Tripathi - University of Iowa
Madeleine M. Allen - University of Iowa
Li Wu - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
Edition: 1.1
DOI: 10.64898/2026.08.03.742552
PMID: 42620025
PMCID: PMC13484655
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory
Number of pages: 60
Language: English
Date posted: 08/04/2026
Academic Unit: Microbiology and Immunology
Record Identifier: 9985219915302771

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