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Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis.sup.1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance.sup.6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment--which contributes to virologic failure, resistance generation and viral transmission--as well as of pre-exposure prophylaxis, leading to new infections.sup.1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence.sup.10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log.sub.10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection., Author(s): John O. Link [sup.1] , Martin S. Rhee [sup.1] , Winston C. Tse [sup.1] [sup.8] , Jim Zheng [sup.1] , John R. Somoza [sup.1] , William Rowe [sup.1] , [...]

Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of protective human antibodies from several individuals recognizing the trimer interface (TI) of the influenza A HA head, a recently identified site of vulnerability. We examined the sequence of Tl-reactive antibodies, determined crystal structures for TI antibody-antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza A HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody-antigen interaction suggests that the TI epitope might serve as an important target for structure-based vaccine design., Introduction Influenza A virus (IAV) is one of the most common causes of severe lower respiratory illness in humans and exhibits a wide antigenic diversity in circulating field strains. Seasonal [...]

Author(s): Robert N. Kirchdoerfer [1]; Christopher A. Cottrell [1]; Nianshuang Wang [2]; Jesper Pallesen [1]; Hadi M. Yassine [3]; Hannah L. Turner [1]; Kizzmekia S. Corbett [3]; Barney S. Graham [...]

Author(s): Gabriel L. Butterfield [1, 2, 3]; Marc J. Lajoie [1, 2]; Heather H. Gustafson [4, 5]; Drew L. Sellers [4, 5, 6]; Una Nattermann [1, 2, 7]; Daniel Ellis [...]