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HIV transmission dynamics and population-wide drug resistance in rural South Africa
There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.
- Steven A. Kemp
- , Kimia Kamelian
- & Ravindra K. Gupta
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Article
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Synergistic effect of two human-like monoclonal antibodies confers protection against orthopoxvirus infection
In this study, the authors show that a single dose of a combination of two human-like monoclonal antibodies protect mice in therapeutic treatment against challenges with ectromelia virus and monkeypox virus. Combination treatment provided more effective viral clearance than single antibody treatment.
- Hadas Tamir
- , Tal Noy-Porat
- & Tomer Israely
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Nucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus
There are limited treatment options for infection with Crimean-Congo hemorrhagic fever virus in humans. Here, the authors show that a monoclonal antibody targeting the highly conserved viral nucleocapsid protein provides protective effects in a mouse model of infection.
- Aura R. Garrison
- , Vanessa Moresco
- & Joseph W. Golden
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Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.
- Joseph F. Standing
- , Laura Buggiotti
- & Francis Yongblah
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Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets
Measles virus infection causes immunosuppression and it’s unclear whether this can be prevented by antivirals. Here, using a canine distemper virus ferret model, the authors show that measles-like immune amnesia and lethal exacerbated respiratory disease after consecutive respiratory virus infections can be mitigated by oral antiviral therapy initiated at the onset of primary clinical signs.
- Robert M. Cox
- , Josef D. Wolf
- & Richard K. Plemper
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Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants
Most recent SARS-CoV-2 variants showed exceptional immune evasion properties. Here, the authors identify a highly conserved epitope within the RBD targeted by a broad spectrum neutralizing antibody BA7535 that shows therapeutic antiviral potency in mouse studies.
- Yanqun Wang
- , An Yan
- & Jincun Zhao
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A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential
The ongoing emergence of highly pathogenic viruses that evade immune-based therapies or lack interventions mandates new approaches, especially for on-demand prophylaxis. Here the authors provide a stapled lipopeptide platform for the rapid development of viral fusion inhibitors to combat outbreaks.
- Gregory H. Bird
- , J. J. Patten
- & Loren D. Walensky
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Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
In this study, the authors report the structure-based discovery and preclinical evaluation of 2 simnotrelvir, an orally bioavailable 3CLpro inhibitor that blocks replication of SARS-CoV-2 variants in 3 vitro, shows robust efficacy in a mouse model and good safety and pharmacokinetic profiles in rats 4 and monkeys.
- Xiangrui Jiang
- , Haixia Su
- & Yechun Xu
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A human monoclonal antibody binds within the poliovirus receptor-binding site to neutralize all three serotypes
Cross-neutralizing activity of monoclonal antibodies against poliovirus serotypes is less commonly reported. In this study, the authors use high-resolution cryo-EM to reveal that a cross-neutralizing human antibody neutralizes all three poliovirus serotypes by interacting with the receptor-binding region, called the canyon.
- Andrew J. Charnesky
- , Julia E. Faust
- & Susan L. Hafenstein
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Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
There are currently no treatment options for infection with Rift Valley fever virus (RVFV). Here, Chapman et al., show that a combination of human monoclonal antibodies targeting two different steps in early virus cell entry enhances protection in a mouse model and is effective at low doses.
- Nathaniel S. Chapman
- , Ruben J. G. Hulswit
- & James E. Crowe Jr.
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Article
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An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants
In this study, the authors report the development of an inhalable IgM-like ACE2 and show that it broadly neutralizes SARS-CoV-2 variants, lowers viral loads and lung pathology in hamsters when administered early, and has good safety profiles in rats and monkeys.
- Juan Liu
- , Fengfeng Mao
- & Wenhui Li
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In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir
Ensitrelvir is an oral antiviral agent that targets SARS-CoV-2 and is clinically useful against infection with omicron variants. The authors characterized mutant viruses with reduced sensitivity to ensitrelvir in vitro and in vivo.
- Maki Kiso
- , Seiya Yamayoshi
- & Yoshihiro Kawaoka
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Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections
One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.
- Wanwisa Promsote
- , Ling Xu
- & Richard A. Koup
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Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2
There are currently two types of antiviral drugs – neutralizing antibodies and small molecule inhibitors. Here, the authors report the development of bicyclic peptides that combine the advantages of both and show their antiviral capacity against SARS-CoV-2 in vitro as well as in small animal models.
- Katherine U. Gaynor
- , Marina Vaysburd
- & Leo C. James
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Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2
Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.
- Nobuyo Higashi-Kuwata
- , Kohei Tsuji
- & Hiroaki Mitsuya
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Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
In this study, the authors developed an ultra-long-acting injectable, biodegradable, and removable in-situ forming implant delivering cabotegravir (CAB ISFI). CAB ISFI was well tolerated and protected against multiple rectal SHIV challenges in female macaques.
- Isabella C. Young
- , Ivana Massud
- & S. Rahima Benhabbour
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Article
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Cellular glycan modification by B3GAT1 broadly restricts influenza virus infection
Identification of host antiviral restriction factors could provide targets for antiviral therapy. Here, using a genome-wide CRISPR screen, the authors identify the glycosyltransferase B3GAT1 as a host protein which, when ectopically overexpressed, restricts influenza virus infection in vitro and in mice, as well as other viruses relying on sialic acid for entry.
- Joseph D. Trimarco
- , Sarah L. Nelson
- & Nicholas S. Heaton
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Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial
Many survivors of COVID-19 experience persistent symptoms, continuing beyond three months from the onset of infection. In this study, authors investigate the effect of remdesivir on recovery and long-COVID-19 symptoms, as well as quality of life and other symptom outcomes, in the 1-year follow-up of a randomised trial.
- Olli P. O. Nevalainen
- , Saana Horstia
- & Kari A. O. Tikkinen
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SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model
Molnupiravir was the first orally available SARS-CoV-2 antiviral approved for outpatient use against SARS-CoV-2, but its efficacy against variants of concern, especially delta, was questioned. Here the authors evaluate molnupiravir against variant of concern in numerous models, including human airway epithelium organoids, ferrets and Roborovski dwarf hamsters.
- Carolin M. Lieber
- , Robert M. Cox
- & Richard K. Plemper
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An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA
Here, Zhao et al. characterize the anti-viral effect of the compound APL-16-5, which is originally derived from the plant endophytic fungus Aspergillus, on Influenza A virus infection in vitro and in vivo. They find that APL-16-5 binds to the E3 ligase TRIM25 and viral polymerase subunit PA and therewith mediates ubiquitination of PA and subsequent proteasome-mediated degradation.’
- Jianyuan Zhao
- , Jing Wang
- & Shan Cen
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De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report
Here, the authors identify and validate the emergence of a SARS-CoV-2 resistance mutation to Remdesivir, associated with virological recrudesce in an immunocompromised patient with persistent COVID-19.
- Shiv Gandhi
- , Jonathan Klein
- & Albert I. Ko
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The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern
There is an urgent need for anti-virals targeting SARS-CoV-2. One of the most promising viral targets is the main protease of SARS-CoV-2, which is essential for viral replication and has no human analogue. Here, Abdelnabi et al. show that one of the most promising anti-virals (PF-07321332), currently in clinical trials, protects against SARS-CoV-2 alpha, beta and delta variant infection and provide evidence of reduced transmission.
- Rana Abdelnabi
- , Caroline S. Foo
- & Johan Neyts
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Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir
DEAD-box polypeptide 3 (DDX3) is a host protein belonging to the family of ATP-dependent RNA helicases. Here, the authors demonstrate that DDX3 inhibitors reverse HIV-1 latency and selectively induce cell death in HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1.
- Shringar Rao
- , Cynthia Lungu
- & Tokameh Mahmoudi
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Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model
While vaccines protecting against SARS-CoV-2 infection are approved, currently, there are no drugs suitable for high-risk exposure use against SARS-CoV-2. Here, Rosenke et al. provide evidence that orally delivered MK-4482, a nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model.
- Kyle Rosenke
- , Frederick Hansen
- & Michael A. Jarvis
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Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin
SARS-CoV-2 expresses a 2′-O RNA methyltransferase (MTase) that is involved in the viral RNA cap formation and therefore a target for antiviral therapy. Here the authors provide the structure of nsp10-nsp16 with the panMTase inhibitor sinefungin and report that the development of MTase inhibitor therapies that target multiple coronoaviruses is feasible.
- Petra Krafcikova
- , Jan Silhan
- & Evzen Boura
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Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
Remdesivir (RDV) is a broad-spectrum antiviral drug with activity against MERS coronavirus, but in vivo efficacy has not been evaluated. Here, the authors show that RDV has superior anti-MERS activity in vitro and in vivo compared to combination therapy with lopinavir, ritonavir and interferon beta and reduces severe lung pathology.
- Timothy P. Sheahan
- , Amy C. Sims
- & Ralph S. Baric
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Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.
- Mélissanne de Wispelaere
- , Guangyan Du
- & Priscilla L. Yang
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Article
| Open Access
Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly
Current treatments for chronic hepatitis B virus (HBV) infection are not curative. Here, the authors show that an antifungal drug, ciclopirox, inhibits HBV capsid assembly and synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model.
- Jung-Ah Kang
- , Songwon Kim
- & Sung-Gyoo Park
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Article
| Open Access
Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection
Long-acting formulation of the integrase inhibitor cabotegravir (CAB LA) is in clinical development for HIV pre-exposure prophylaxis (PrEP). Here, using a SHIV macaque model, the authors show emergence of integrase mutations associated to CAB LA PrEP that confer pan-integrase inhibitor resistance.
- Jessica Radzio-Basu
- , Olivia Council
- & J. Gerardo García-Lerma
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Phosphoproteomic-based kinase profiling early in influenza virus infection identifies GRK2 as antiviral drug target
Influenza A virus (IAV) causes annual epidemics and development of antivirals is needed. Here, the authors perform phosphoproteomics during IAV entry and identify GRK2 as drug target, inhibition of which decreases replication of seasonal and pandemic IAV in primary human cells and animal models.
- Emilio Yángüez
- , Annika Hunziker
- & Silke Stertz
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Article
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In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity
Broadly neutralizing antibodies (bnAbs) against influenza hemagglutinin (HA) have yielded insights for antiviral development. Here, the authors employ saturated mutagenesis of the paratope region of a bnAb combined with yeast display screening using H1 and H3 HAs, and find that a tradeoff exists between Ab affinity and breadth that influenced by disparate modes of receptor binding.
- Nicholas C. Wu
- , Geramie Grande
- & Ian A. Wilson
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ASK1 restores the antiviral activity of APOBEC3G by disrupting HIV-1 Vif-mediated counteraction
The human protein APOBEC3G (A3G) inhibits HIV-1 replication, but the viral protein Vif counteracts by inducing A3G degradation. Here Miyakawa et al. show that the antiretroviral drug AZT restores A3G function in vitroby stimulating expression of a host protein, ASK1, which interferes with the action of Vif.
- Kei Miyakawa
- , Satoko Matsunaga
- & Akihide Ryo
An effective and rapidly degradable disinfectant from disinfection byproducts