# Macrophage makeover extreme viral edition: mechanisms of immune subversion and therapeutic perspectives

**Authors:** Zoé Fremont-Debaene, Suzanne Faure-Dupuy

PMC · DOI: 10.1099/jgv.0.002228 · The Journal of General Virology · 2026-02-23

## TL;DR

This paper reviews how viruses manipulate macrophages to evade the immune system and explores new therapies to restore immune function.

## Contribution

The paper provides a comprehensive review of viral strategies to subvert macrophage functions and highlights novel therapeutic approaches.

## Key findings

- Viruses modulate macrophage functions to evade immune clearance and promote infection.
- Excessive or suppressed cytokine production by viruses leads to immunopathology or immune evasion.
- New therapies targeting macrophage functionality show promise in treating viral infections.

## Abstract

Macrophages are versatile innate immune cells that play a crucial role in immune responses and tissue repair. However, their plasticity and central role in immunity also make them prime targets for viral manipulation. Viruses have evolved sophisticated mechanisms to modulate macrophage functions, disrupting cytokine secretion and phagocytosis to evade immune clearance, establish infection and promote persistence. For instance, some viruses drive excessive cytokine secretion, resulting in hyperinflammation and tissue damage, while other viruses suppress cytokine production and impair phagocytic activity to evade detection. These disruptions often result in systemic immunopathology, chronic inflammation or the establishment of viral reservoirs. Emerging therapeutic strategies aiming to restore macrophage functionality through direct-acting antivirals or macrophage-specific interventions represent a growing interest. These novel approaches offer promising perspectives for combating viral-induced macrophage dysfunction. By summarizing the interplay between viruses and macrophages, this review highlights critical pathways of immune modulation and underscores innovative therapeutic strategies to restore immune balance, offering hope for combating viral infections and their associated pathologies.

## Full-text entities

- **Genes:** EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2) [NCBI Gene 5610] {aka PKR, PPP1R83, PRKR}, AIC (Aicardi syndrome) [NCBI Gene 192], IFNB1 (interferon beta 1) [NCBI Gene 3456] {aka IFB, IFF, IFN-beta, IFNB}, TLR7 (toll like receptor 7) [NCBI Gene 51284] {aka IMD74, SLEB17, TLR7-like}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, CSF1R (colony stimulating factor 1 receptor) [NCBI Gene 1436] {aka BANDDOS, C-FMS, CD115, CSF-1R, CSFR, FIM2}, IFI16 (interferon gamma inducible protein 16) [NCBI Gene 3428] {aka IFNGIP1, PYHIN2}, TIRAP (TIR domain containing adaptor protein) [NCBI Gene 114609] {aka BACTS1, Mal, MyD88-2, wyatt}, NLRC4 (NLR family CARD domain containing 4) [NCBI Gene 58484] {aka AIFEC, CARD12, CLAN, CLAN1, CLANA, CLANB}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, CD47 (CD47 molecule) [NCBI Gene 961] {aka IAP, MER6, OA3}, ORF3a (ORF3a protein) [NCBI Gene 43740569], HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004] {aka C6orf150, D4, MB21D1, h-cGAS}, IRF7 (interferon regulatory factor 7) [NCBI Gene 3665] {aka IMD39, IRF-7, IRF-7H, IRF7A, IRF7B, IRF7C}, DHX58 (DExH-box helicase 58) [NCBI Gene 79132] {aka D11LGP2, D11lgp2e, LGP2, RLR-3}, CSF2 (colony stimulating factor 2) [NCBI Gene 1437] {aka CSF, GMCSF}, ARPIN (actin related protein 2/3 complex inhibitor) [NCBI Gene 348110] {aka C15orf38}, CD86 (CD86 molecule) [NCBI Gene 942] {aka B7-2, B7.2, B70, BU63, CD28LG2, CD86 v6}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CCR5 (C-C motif chemokine receptor 5) [NCBI Gene 1234] {aka CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 3627] {aka C7, IFI10, INP10, IP-10, SCYB10, crg-2}, STAT2 (signal transducer and activator of transcription 2) [NCBI Gene 6773] {aka IMD44, ISGF-3, P113, PTORCH3, STAT113}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, IRF3 (interferon regulatory factor 3) [NCBI Gene 3661] {aka IIAE7}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, TICAM1 (TIR domain containing adaptor molecule 1) [NCBI Gene 148022] {aka IIAE6, MyD88-3, PRVTIRB, TICAM-1, TRIF}, CXCL9 (C-X-C motif chemokine ligand 9) [NCBI Gene 4283] {aka CMK, Humig, MIG, SCYB9, crg-10}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, IRF9 (interferon regulatory factor 9) [NCBI Gene 10379] {aka IRF-9, ISGF3, ISGF3G, p48}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IKBKE (inhibitor of nuclear factor kappa B kinase subunit epsilon) [NCBI Gene 9641] {aka IKK-E, IKK-i, IKKE, IKKI}, IFNA8 (interferon alpha 8) [NCBI Gene 3445] {aka IFN-alphaB}, TLR3 (toll like receptor 3) [NCBI Gene 7098] {aka CD283, IIAE2, IMD83}, TLR9 (toll like receptor 9) [NCBI Gene 54106] {aka CD289}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, CD80 (CD80 molecule) [NCBI Gene 941] {aka B7, B7-1, B7.1, BB1, CD28LG, CD28LG1}, KLF4 (KLF transcription factor 4) [NCBI Gene 9314] {aka EZF, GKLF}, Nef [NCBI Gene 156110], ARL5B (ARF like GTPase 5B) [NCBI Gene 221079] {aka ARL8}, TBK1 (TANK binding kinase 1) [NCBI Gene 29110] {aka AIARV, FTDALS4, IIAE8, NAK, T2K}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, TRIM63 (tripartite motif containing 63) [NCBI Gene 84676] {aka CMH31, IRF, MURF1, MURF2, RNF28, SMRZ}, MAVS (mitochondrial antiviral signaling protein) [NCBI Gene 57506] {aka CARDIF, IPS-1, IPS1, VISA}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, TLR2 (toll like receptor 2) [NCBI Gene 7097] {aka CD282, TIL4}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, IFNAR1 (interferon alpha and beta receptor subunit 1) [NCBI Gene 3454] {aka AVP, CRF2-1, IFN-R-1, IFN-alpha-REC, IFNAR, IFNBR}, Vpu [NCBI Gene 155945], IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, RIGI (RNA sensor RIG-I) [NCBI Gene 23586] {aka DDX58, RIG-I, RIG1, RLR-1, SGMRT2}, IFIH1 (interferon induced with helicase C domain 1) [NCBI Gene 64135] {aka AGS7, Hlcd, IDDM19, IMD95, MDA-5, MDA5}, ATF2 (activating transcription factor 2) [NCBI Gene 1386] {aka CRE-BP1, CREB-2, CREB2, HB16, TREB7}, NAIP (NLR family apoptosis inhibitory protein) [NCBI Gene 4671] {aka BIRC1, NLRB1, psiNAIP}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}
- **Diseases:** immune dysregulation (OMIM:614878), HIV (MESH:D015658), infectious disease (MESH:D003141), chronic (MESH:D002908), bacterial infections (MESH:D001424), inflammatory cytokines (MESH:D000080424), systemic (MESH:D015619), Infection (MESH:D007239), COVID-19 (MESH:D000086382), MDMs (MESH:D055501), HCV infection (MESH:D006526), viral diseases (MESH:D014777), systemic lupus erythematosus (MESH:D008180), respiratory (MESH:D012131), CMV (MESH:D003586), haemorrhagic fevers (MESH:D006470), autoimmune diseases (MESH:D001327), multi-organ failure (MESH:D009102), DENV (MESH:D003715), COPD (MESH:D029424), opportunistic infections (MESH:D009894), HBV and (MESH:D006509), NLRs (MESH:D020191), chronic inflammation (MESH:D007249)
- **Chemicals:** guanosine (MESH:D006151), ROS (MESH:D017382), ATP (MESH:D000255), cGAMP (MESH:C584311), velpatasvir (MESH:C000604171), oseltamivir (MESH:D053139), DAAs (-), imdevimab (MESH:C000711488), Na (MESH:D012964), maraviroc (MESH:D000077592), NO (MESH:D009569), casirivimab (MESH:C000711487), sofosbuvir (MESH:D000069474), voxilaprevir (MESH:C000619503), ganciclovir (MESH:D015774), sialic acid (MESH:D019158), remdesivir (MESH:C000606551), Oxygen (MESH:D010100)
- **Species:** Influenza A virus (no rank) [taxon 11320], Cytomegalovirus (genus) [taxon 10358], West Nile virus (no rank) [taxon 11082], DNA viruses [taxon 2080735], Dengue virus (no rank) [taxon 12637], rhinovirus A16 (no rank) [taxon 31708], Homo sapiens (human, species) [taxon 9606], Orthomyxoviridae (family) [taxon 11308], Respiratory syncytial virus (no rank) [taxon 12814], Hepatitis B virus (no rank) [taxon 10407], Human immunodeficiency virus 1 (no rank) [taxon 11676], Orthopoxvirus vaccinia (species) [taxon 10245], Salmonella enterica subsp. enterica serovar Typhimurium (no rank) [taxon 90371], Severe acute respiratory syndrome coronavirus 2 (no rank) [taxon 2697049], Acanthamoeba polyphaga mimivirus (no rank) [taxon 212035], Human alphaherpesvirus 1 (Herpes simplex virus type 1, no rank) [taxon 10298], Zika virus (no rank) [taxon 64320], hepatitis C virus [taxon 11103]
- **Mutations:** A46R

## Full text

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## Figures

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## References

153 references — full list in the complete paper: https://tomesphere.com/paper/PMC12928704/full.md

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Source: https://tomesphere.com/paper/PMC12928704