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HIV-1

  • Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes
    Antiviral Agents
    Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes

    Lenacapavir (LEN; GS-6207) is a potent first-in-class inhibitor of HIV-1 capsid with long-acting properties and the potential for subcutaneous dosing every 3 months or longer. In the clinic, a single subcutaneous LEN injection (20 mg to 750 mg) in people with HIV (PWH) induced a strong antiviral response, with a >2.3 mean log10 decrease in HIV-1 RNA at day 10.

    Nicolas Margot, Renee Ram, Martin Rhee, Christian Callebaut
  • Epigenetic Compound Screening Uncovers Small Molecules for Reactivation of Latent HIV-1
    Antiviral Agents
    Epigenetic Compound Screening Uncovers Small Molecules for Reactivation of Latent HIV-1

    During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established that circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically indistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of...

    Ariane Zutz, Lin Chen, Franziska Sippl, Andreas Humpe, Christian Schölz
  • Rapid-Release Griffithsin Fibers for Dual Prevention of HSV-2 and HIV-1 Infections
    Antiviral Agents
    Rapid-Release Griffithsin Fibers for Dual Prevention of HSV-2 and HIV-1 Infections

    The biologic griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs), including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO),...

    Kevin M. Tyo, Amanda B. Lasnik, Longyun Zhang, Alfred B. Jenson, Joshua L. Fuqua, Kenneth E. Palmer, Jill M. Steinbach-Rankins
  • Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response
    Antiviral Agents
    Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response

    Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. The “shock and kill” strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although...

    Wen Peng, Zhongsi Hong, Xi Chen, Hongbo Gao, Zhuanglin Dai, Jiacong Zhao, Wen Liu, Dan Li, Kai Deng
  • Antiviral Activity of Tenofovir Alafenamide against HIV-1 with Thymidine Analog-Associated Mutations and M184V
    Antiviral Agents
    Antiviral Activity of Tenofovir Alafenamide against HIV-1 with Thymidine Analog-Associated Mutations and M184V

    Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are prodrugs of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). In vivo, TAF achieves >4-fold-higher intracellular levels of TFV diphosphate (TFV-DP) compared to TDF. Since thymidine analog-associated mutations (TAMs) in HIV-1 confer reduced TFV susceptibility, patients with TAM-containing HIV-1 may benefit from higher TFV-DP levels...

    Nicolas Margot, Renee Ram, Michael Abram, Richard Haubrich, Christian Callebaut
  • Reciprocal Modulation of Antiretroviral Drug and Steroid Receptor Function <em>In Vitro</em>
    Antiviral Agents
    Reciprocal Modulation of Antiretroviral Drug and Steroid Receptor Function In Vitro

    Millions of women are exposed simultaneously to antiretroviral drugs (ARVs) and progestin-based hormonal contraceptives. Yet the reciprocal modulation by ARVs and progestins of their intracellular functions is relatively unexplored.

    Sigcinile Dlamini, Michael Kuipa, Kim Enfield, Salndave Skosana, John G. Woodland, Johnson Mosoko Moliki, Alexis J. Bick, Zephne van der Spuy, Michelle F. Maritz, Chanel Avenant, Janet P. Hapgood
  • Open Access
    Doravirine Exposure and HIV-1 Suppression after Switching from an Efavirenz-Based Regimen to Doravirine-Lamivudine-Tenofovir Disoproxil Fumarate
    Antiviral Agents
    Doravirine Exposure and HIV-1 Suppression after Switching from an Efavirenz-Based Regimen to Doravirine-Lamivudine-Tenofovir Disoproxil Fumarate

    Doravirine is a nonnucleoside reverse transcriptase inhibitor that has been approved for the treatment of HIV-1. In a phase 1 trial, doravirine exposure was transiently decreased when treatment was started immediately after the cessation of efavirenz treatment.

    Wayne Greaves, Hong Wan, Ka Lai Yee, Bhargava Kandala, Pavan Vaddady, Carey Hwang
  • An Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase Inhibitors
    Antiviral Agents
    An Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase Inhibitors

    Viral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or...

    Kristof Theys, Pieter J. K. Libin, Kristel Van Laethem, Ana B. Abecasis
  • Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications
    Antiviral Agents
    Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications

    There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF...

    Masayuki Amano, Pedro Miguel Salcedo-Gómez, Ravikiran S. Yedidi, Rui Zhao, Hironori Hayashi, Kazuya Hasegawa, Tomofumi Nakamura, Cuthbert D. Martyr, Arun K. Ghosh, Hiroaki Mitsuya
  • Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants
    Antiviral Agents
    Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants

    We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 have meta-monofluorophenyl and para-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50...

    Shin-ichiro Hattori, Hironori Hayashi, Haydar Bulut, Kalapala Venkateswara Rao, Prasanth R. Nyalapatla, Kazuya Hasegawa, Manabu Aoki, Arun K. Ghosh, Hiroaki Mitsuya

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