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Antiviral Research

Publisher:
Elsevier
ISSN:
0166-3542
Category:
VIROLOGY
Impact factor:
—
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50 parsed articles

Last update: 2026-10-28

Latest articles

Field-isolate recombinant tick-borne encephalitis viruses define reporter-stability guidelines for antiviral testing in flaviviruses

2026-11-30

Benoit Besson, Damien Mouton, Yamina Boukenadel, Theo Nass, Soonju Park, Nakyung Lee, Jianhui Li, David Shum, Redmond Smyth, Stefanie C. Becker, Carine Meignin, Sébastien Pfeffer

As arthropod-borne viruses continue to threaten populations globally, there is a pressing need for experimental systems that enable rapid antiviral discovery. Reverse-genetics platforms producing recombinant reporter orthoflaviviruses have been developed to address this gap. Here, we present two new recombinant tick-borne encephalitis viruses (TBEVrec) generated on a European-subtype Haselmühl Tiho1 isolate backbone. A reporter gene, either eGFP or Nluc, was inserted in the capsid-coding region of the genome downstream of the capsid RNA regulatory signal and separated from the complete viral polyprotein by a 2A self-cleaving peptide. TBEVrec was better rescued using the circular polymerase extension reaction (CPER) than with the infectious subgenomic amplicon (ISA) method. TBEVrec replicated efficiently in relevant human cell lines, with comparable replication to wild-type TBEV in a neuronal cell line and moderately reduced titers and RNA levels in immune-derived cell lines. Using either eGFP or Nluc, we illustrate how TBEVrec enabled high-content RNAi screening, highlighting Nucleolin and PRKD1 as potential TBEV host factors, and drug testing on a benchtop plate reader. Nanopore sequencing of the eGFP insert revealed that the reporter is excised without affecting flanking regions. Comparative analysis of eGFP and Nluc further shows that this instability is time- and cell type-dependent, and that Nluc is comparatively more stable. From these observations, we outline safeguards and design principles that are broadly applicable both to the rescue of existing constructs and to the design of future recombinant reporter virus platforms.

DOI: 10.1016/j.antiviral.2026.106528

N70 S/Y155H combined mutation of neuraminidase of avian influenza H9N2 virus confers oseltamivir and zanamivir resistance and pathogenicity to mice

2026-11-30

Shenyu Ma, Yuting Chen, Jianwen Zhu, Yuhan Zong, Keyu Cai, Zhonglong Yang, Wenlei Wang, Yunfei Guo, Yan Guo, Xinyue Duan, Ziyan Fang, Nan Zhu, Sujuan Chen, Pinghu Zhang

Recently, H9N2 avian influenza virus (AIV) poses a significant threat to both the poultry industry and public health. Therefore, investigating the impact of its neuraminidase mutations on susceptibility to neuraminidase inhibitors (NAIs) is of great importance for clinically preventing potential cross-species transmission of H9N2. In this study, our results revealed that NAI resistance-related mutations of most H9N2 viruses isolated from China during 1998 to 2024 mainly occurred at positions N70S, E119 A/D/G/V, Q133K, Q136A, D151E, Y155H, I222V, R224K, E276D, R292K, N294S, and R371K. Among them, the combined N70S and Y155H mutations are common characteristics of H9N2 viruses circulating in recent years. In vivo experiments demonstrated that these H9N2 viruses harboring the combined N70S and Y155H mutations exhibit high pathogenicity to BALB/c mice without prior adaption. In vitro neuraminidase inhibition assays confirmed that these H9N2 viruses bearing the N70 S/Y155H mutations exhibited greater reduced inhibition than their counterparts bearing the N70S or Y155H single mutation to oseltamivir and zanamivir, but remained highly sensitive to peramivir. Notably, the in vivo protective effect of NAIs against H9N2 virus with combined N70S and Y155H mutations is limited, possibly due to the restricted ability of these drugs to ameliorate the excessive inflammatory responses. Therefore, there is an urgency to strengthen research on epidemiological surveillance and prevention strategies for avian influenza H9N2 harboring these mutations.

DOI: 10.1016/j.antiviral.2026.106540

Molnupiravir, first small molecule therapeutic to demonstrate therapeutic efficacy against Venezuelan equine encephalitis virus in the cynomolgus macaque model

2026-11-30

Christina L. Gardner, Lisa Pieterse, Ashley E. Piper, Elaine S. Cerchin, Franco Rossi, Weam I. Zaky, Bobby J. Curry, Michael Ward, Sarah K. Cudd, William A. Baskerville, Sarah Norris, J. Matthew Meinig, Crystal W. Burke

Venezuelan equine encephalitis virus (VEEV) is an emergent arbovirus of major epidemic concern. Associated with periodic outbreaks in Central and South America, VEEV has a high morbidity rate in humans due to a 1:1 clinical-to-subclinical ratio and can cause neurological disease in up to 14% of cases. Concerningly, no FDA-approved vaccines or therapeutics for VEEV exist. Molnupiravir, an isopropyl ester prodrug of β-D-N4-hydroxycytidine, has previously showcased notable antiviral activity against VEEV in vitro and in rodents. While molnupiravir emergency use authorization has been granted for SARS-CoV-2, drug efficacy against VEEV in a translational model of human disease has yet to be investigated. We therefore performed the first study examining molnupiravir efficacy against VEEV in cynomolgus macaques, a non-lethal animal model known to reiterate clinical hallmarks of VEEV human disease. Animals treated twice-daily with 150 mg/kg molnupiravir approximately 8 h post-VEEV exposure demonstrated improved human-relevant clinical parameters, including reduced viremia, febrile illness, and lymphopenia, as well as diminished histopathological evidence of encephalitis and cerebral RNA persistence. We additionally showcased that the calculated human equivalent dose of molnupiravir (97 mg/kg BID) was insufficient in decreasing viremia or improving clinical parameters. Our study is the first to characterize a small molecule therapeutic as an effective treatment against VEEV in a macaque model accurately recapitulating human VEEV disease [Words: 215].

DOI: 10.1016/j.antiviral.2026.106548

Identification of novel HIV-1 capsid protein (CA) inhibitors (ACAi-010 and ACAi-024) that promote hyper-stabilization of HIV-1 CA in vitro

2026-11-30

Masayuki Amano, Tomofumi Nakamura, Toshikazu Miyakawa, Hirotomo Nakata

The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) is a vital viral component and an attractive antiviral target. Our prior research demonstrated that amino acid (AA)-inserts at certain positions within the HIV-1 CA result in significant CA degradation, and that such AA-insert-containing HIV-1 have significantly compromised infectivity/replicability. We posited that this degradation arises from conformational or structural-incompatibility introduced by the AA-inserts at particular sites within the CA. We also hypothesized that a compound tightly bound to certain CA domains where influence CA-stability, might alter CA-stability and inhibit viral-replication. In the current research, we initially explored compounds which can bind to such domains upon the CA by virtual docking simulations, utilizing a library comprising >six million compounds. For compounds with good docking-scores, we evaluated anti-HIV-1-capacity using HIV-1 LAI . Through these methods, we identified ACAi-010 and ACAi-024, designed as CA hyper-stabilizers, exhibiting potent antiviral-activity against a broad-spectrum of HIV-1/2, containing multi-drug-resistant and CA inhibitor-resistant strains, with least cytotoxicity. We confirmed that ACAi-010/ACAi-024 induced hyper-stabilization of HIV-1 CA through ELISA using lysates from cells expressing CA-monomer or HIV-1, and through differential scanning fluorimetry. Transmission electron microscopy revealed morphological-alterations in HIV-1 virions exposed to ACAi-010/ACAi-024. HIV-1 generated with CA hyper-stabilizers exhibited disrupted replicability/infectivity, as evaluated by p24 assay/MAGI assay. We found that ACAi-010/ACAi-024 did not inhibit HIV-1 reverse-transcriptase. Finally, drug-selection experiments indicated that the emergence of ACAi-010/ACAi-024-resistant-HIV-1 was severely difficult or failed. Our findings suggest that the CA hyper-stabilizers we identified/evaluated may lead to novel and effective interventions against HIV-1, including drug-resistant-variants.

DOI: 10.1016/j.antiviral.2026.106552

The Golgi-resident protein ACBD3 facilitates the interaction between enteroviral 3A proteins and Exportin-1

2026-11-30

Vladimira Horova, Michala Zgarbova, Martin Klima, Jan Silhan, Evzen Boura

Enteroviruses are among the most common viral pathogens in humans, causing illnesses ranging from the common cold to severe and sometimes life-threatening diseases such as acute haemorrhagic conjunctivitis or poliomyelitis. To replicate efficiently within host cells, enteroviruses hijack several host factors, including the lipid kinase PI4KB and the adaptor protein ACBD3. During infection, ACBD3 is recruited to viral replication sites through a direct interaction between its C-terminal GOLD domain and viral non-structural 3A proteins. Here, we identify exportin 1 (XPO1) as a host factor involved in enteroviral replication. We demonstrate that 3A proteins of various enteroviruses recruit the host proteins ACBD3 and XPO1 to form a stable ternary complex. Chemical inhibition of XPO1 with selinexor (originally developed as an anti-cancer medication), significantly attenuates coxsackievirus B3 replication in human cells. Consequently, our study identifies XPO1 as a host target for potential anti-enteroviral interventions, highlighting an immediate opportunity for drug repurposing.

DOI: 10.1016/j.antiviral.2026.106547

Novel phorbol-12- O -octoate derivatives exert a dual effect by inhibiting de novo HIV-1 infection and reactivating latent virus

2026-11-30

Meng-Di Ma, Mao Sun, Duo-Zhi Chen, Rong-Hua Luo, Hong-Yi Zheng, Liu-Meng Yang, Tian-Zhang Song, Hong Liang, Xiao-Jiang Hao, Yong-Tang Zheng

Viral reservoirs represent the primary obstacle to achieving a cure for HIV-1 infection, as viral replication rebounds after interruption of antiretroviral therapy (ART). To identify promising dual-effect phorbol-12-O-octoate derivatives capable of both effectively inhibiting viral replication in acute HIV-1 infection and reactivating latent HIV-1, we designed, synthesized, and evaluated a new series of phorbol esters and explored their underlying mechanisms. HPB-5073 was identified as a promising candidate that inhibits HIV-1 replication at nanomolar concentrations. Further analysis revealed that HPB-5073 reduces the expression of the HIV-1 entry receptor CD4 and co-receptor CXCR4 and impairs the formation of the early reverse transcription intermediate, -ssDNA, indicating that it targets early steps of the HIV-1 life cycle, including viral entry and early post-entry replication. Meanwhile, HPB-5073 effectively reversed HIV-1 latency in both latently infected cell lines and PBMCs from people living with HIV-1 (PLWH) on ART, with minimal cytotoxicity. Mechanistically, HPB-5073 induced the initiation and elongation of HIV-1 LTR transactivation, thereby reactivating latent HIV-1 transcription by modulating the interaction of EGR1 and Tat with the HIV-1 LTR.

DOI: 10.1016/j.antiviral.2026.106551

Intracellular Zn 2+ levels regulate susceptibility to hepatitis B virus infection by modulating NTCP-mediated viral entry

2026-11-30

Yumi Itoh, Chiharu Morita, Cui Jinzi, Tatsuya Suzuki, Aiko Ono, Tomomi Hishinuma, Kento Fukano, Daisuke Okuzaki, Daisuke Motooka, Kei Miyakawa, Yasuyoshi Hatayama, Akihide Ryo, Mitsuyoshi Suzuki, Hajime Takei, Hiroshi Nittono, Tomohisa Tanaka, Koichi Watashi, Masamichi Muramatsu, Kohji Moriishi, Yoshiharu Matsuura

ABSTRACT Hepatitis B virus (HBV) infection remains a significant global health challenge and is a leading cause of chronic liver diseases, including cirrhosis and hepatocellular carcinoma. Although nucleos(t)ide analogs and interferon-based therapies suppress viral replication, they do not eliminate the viral reservoir, highlighting the need for novel therapeutic strategies. HBV utilizes the sodium taurocholate cotransporting polypeptide (NTCP) as a key receptor for hepatocyte entry; however, the underlying mechanisms governing this process remain incompletely understood. In this study, we demonstrate that intracellular Zn 2+ levels, regulated by zinc transporter 1 (ZnT1), also known as solute carrier family 30 member 1 (SLC30A1), serve as critical modulators of HBV entry. Zinc supplementation significantly reduced both HBV and hepatitis D virus infection in NTCP-expressing hepatocytes without affecting post-entry replication steps. Knockout or knockdown of SLC30A1 led to intracellular Zn 2+ accumulation and impaired HBV infection, effects reversed by re-expression of functional SLC30A1 or treatment with the Zn 2+ chelator TPEN. Mechanistically, elevated Zn 2+ levels disrupted NTCP-mediated HBV/HDV internalization and bile acid uptake, implicating Zn 2+ in the regulation of receptor activity. RNA sequencing analysis further revealed transcriptional reprogramming of metabolic and bile acid-associated pathways in Zn 2+ -treated cells. Collectively, these findings reveal a role for intracellular zinc homeostasis in regulating HBV entry and implicate the SLC30A1–Zn2+–NTCP axis in this process.

DOI: 10.1016/j.antiviral.2026.106542

Nucleoside analogs containing an imino-ribitol sugar exhibit a distinctive pattern of interference with RNA synthesis by the Dengue virus polymerase

2026-11-30

Sandesh Deshpande, Anthony J.B. van Hameren, James M. Wood, Rinu Shrestha, Kevin Sparrow, Gary B. Evans, Lawrence D. Harris, Esther M.M. Bulloch, Richard L. Kingston

Iminovirs are antiviral nucleoside analogs in which the naturally occurring ribose sugar is replaced by an imino-ribitol group, linked to the base by a non-native carbon-carbon bond. The prototypical iminovir is galidesivir, an adenosine analog that inhibits replication of a wide range of RNA viruses. Initial investigation of the effects of galidesivir triphosphate on RNA synthesis by the Dengue virus serotype 2 (DENV-2) polymerase showed that the analog was incorporated with reduced efficiency relative to ATP, and incorporation of the analog at consecutive sites in the nascent RNA was effectively blocked. To better understand the origin of these effects, we have extended this work, studying both galidesivir triphosphate and three closely related compounds with variations in both the base and sugar groups. We investigated the effects of these compounds on RNA synthesis using primer extension assays with varying template sequences. Quantitative analysis of the data confirms that the DENV-2 polymerase processes iminovir triphosphates less efficiently than ATP. Galidesivir, for example, is incorporated into the nascent RNA chain around thirteen times slower than adenosine, a difference that is fully ascribable to the presence of the imino-ribitol group. Furthermore, consecutive incorporation of iminovirs is strongly disfavored. Consequently, iminovir triphosphates slow the overall rate of RNA chain extension when present at high concentrations, with this effect modulated by the template sequence. However, iminovir incorporation into the nascent RNA strand does not act to terminate RNA synthesis, which suggests that antiviral activity must result from events downstream of initial incorporation.

DOI: 10.1016/j.antiviral.2026.106541