Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1,2,3,4,5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. 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 infections1,2,4,7,8,9. 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 adherence10. 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 log10-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.
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All data to understand and assess the conclusions of this research are available in the Article and Supplementary Information. Raw gel source data for Fig. 2f are available in Supplementary Fig. 1. Small-molecule X-ray crystallographic coordinates and structure factor files have been deposited in the Protein Data Bank (PDB) with accession number 6V2F. Study GS-US-200-4072 was registered with ClinicalTrials.gov, NCT03739866. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Grant, R. M. et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 363, 2587–2599 (2010).
Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).
Molina, J. M. et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N. Engl. J. Med. 373, 2237–2246 (2015).
Thigpen, M. C. et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N. Engl. J. Med. 367, 423–434 (2012).
WHO. HIV/AIDS Fact Sheets, 15 November 2019. https://www.who.int/news-room/fact-sheets/detail/hiv-aids (WHO, 2019).
Emu, B. et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N. Engl. J. Med. 379, 645–654 (2018).
Bangsberg, D. R. et al. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS 15, 1181–1183 (2001).
Marrazzo, J. M. et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 372, 509–518 (2015).
Anderson, P. L. et al. Emtricitabine–tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci. Transl. Med. 4, 151ra125 (2012).
Gulick, R. M. & Flexner, C. Long-acting HIV drugs for treatment and prevention. Annu. Rev. Med. 70, 137–150 (2019).
Thenin-Houssier, S. & Valente, S. T. HIV-1 capsid inhibitors as antiretroviral agents. Curr. HIV Res. 14, 270–282 (2016).
Carnes, S. K., Sheehan, J. H. & Aiken, C. Inhibitors of the HIV-1 capsid, a target of opportunity. Curr. Opin. HIV AIDS 13, 359–365 (2018).
Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).
Freed, E. O. HIV-1 assembly, release and maturation. Nat. Rev. Microbiol. 13, 484–496 (2015).
Ganser, B. K., Li, S., Klishko, V. Y., Finch, J. T. & Sundquist, W. I. Assembly and analysis of conical models for the HIV-1 core. Science 283, 80–83 (1999).
Yamashita, M. & Engelman, A. N. Capsid-dependent host factors in HIV-1 infection. Trends Microbiol. 25, 741–755 (2017).
Huang, P. T. et al. FEZ1 is recruited to a conserved cofactor site on capsid to promote HIV-1 trafficking. Cell Rep. 28, 2373–2385 (2019).
Fernandez, J. et al. Transportin-1 binds to the HIV-1 capsid via a nuclear localization signal and triggers uncoating. Nat. Microbiol. 4, 1840–1850 (2019).
Carlson, L. A. et al. Three-dimensional analysis of budding sites and released virus suggests a revised model for HIV-1 morphogenesis. Cell Host Microbe 4, 592–599 (2008).
Briggs, J. A., Wilk, T., Welker, R., Kräusslich, H. G. & Fuller, S. D. Structural organization of authentic, mature HIV-1 virions and cores. EMBO J. 22, 1707–1715 (2003).
Yant, S. R. et al. A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. Nat. Med. 25, 1377–1384 (2019).
Graupe, M. et al. Therapeutic compounds. US patent 10,071,985 B2 (2018).
Matreyek, K. A., Yücel, S. S., Li, X. & Engelman, A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 9, e1003693 (2013).
Price, A. J. et al. CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog. 8, e1002896 (2012).
Price, A. J. et al. Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathog. 10, e1004459 (2014).
Bhattacharya, A. et al. Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. Proc. Natl Acad. Sci. USA 111, 18625–18630 (2014).
Lee, K. et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7, 221–233 (2010).
Perrier, M. et al. Prevalence of gag mutations associated with in vitro resistance to capsid inhibitor GS-CA1 in HIV-1 antiretroviral-naive patients. J. Antimicrob. Chemother. 72, 2954–2955 (2017).
Li, G. et al. Functional conservation of HIV-1 Gag: implications for rational drug design. Retrovirology 10, 126 (2013).
Yant, S. R. et al. In vitro resistance profile of GS-6207, a first-in-class picomolar HIV capsid inhibitor in clinical development as a novel long-acting antiretroviral agent. In 10th IAS Conference on HIV Science http://programme.ias2019.org/Abstract/Abstract/683 (IAS, 2019).
Tsiang, M. et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 60, 7086–7097 (2016).
Margot, N. A., Gibbs, C. S. & Miller, M. D. Phenotypic susceptibility to bevirimat in isolates from HIV-1-infected patients without prior exposure to bevirimat. Antimicrob. Agents Chemother. 54, 2345–2353 (2010).
Nakabayashi, H., Taketa, K., Miyano, K., Yamane, T. & Sato, J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 42, 3858–3863 (1982).
Balakrishnan, M. et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE 8, e74163 (2013).
Prichard, M. N. & Shipman, C. Jr. Analysis of combinations of antiviral drugs and design of effective multidrug therapies. Antivir. Ther. 1, 9–20 (1996).
Bam, R. A. et al. TLR7 agonist GS-9620 is a potent inhibitor of acute HIV-1 infection in human peripheral blood mononuclear cells. Antimicrob. Agents Chemother. 61, e01369-16 (2016).
Warren, T. K. et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531, 381–385 (2016).
Hung, M. et al. Large-scale functional purification of recombinant HIV-1 capsid. PLoS ONE 8, e58035 (2013).
Pornillos, O. et al. X-ray structures of the hexameric building block of the HIV capsid. Cell 137, 1282–1292 (2009).
Pornillos, O., Ganser-Pornillos, B. K. & Yeager, M. Atomic-level modelling of the HIV capsid. Nature 469, 424–427 (2011).
Kissinger, C. R., Gehlhaar, D. K. & Fogel, D. B. Rapid automated molecular replacement by evolutionary search. Acta Crystallogr. D 55, 484–491 (1999).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).
We thank D. Cowfer, K. Brendza, G. Czerwieniec, M. Tsiang, K. Wang, G. Lane, M. Kenney, M. Ceo, S. Kazerani, T. Lane, L. Meng, T. Rainey, A. Vandehey, A. Wagner, M. O’Keefe, J. Yoon, S. Neville, W. Lew, B. Ross, Q. Wang, J. Cha, M. Tran and K. Nguyen for their support and contributions, and all the people who participated in the phase-I clinical trials, including the study participants, their families, and the principal investigators and their staff.
All authors are current or previous employees of Gilead Sciences (except for G.I.S., P.J.R., G.E.C., C.K.M., W.I.S. and E.S.D.) and received salary and stock ownership as compensation for their employment. M.G., J.O.L., W.R., R.D.S., S.D.S., W.C.T. and J.R.Z. are inventors on granted US patent no. 10,071,985B2 covering GS-6207 composition of matter and methods of use. G.I.S. receives research support from Gilead Sciences, Janssen Pharmaceutica, GlaxoSmithKline, Abbvie and Cepheid, and is on the speaker’s bureau and advisory board for Janssen, ViiV Healthcare and Merck. G.E.C. receives grants (investigator research payments) from Gilead Sciences, ViiV Healthcare, Merck and Janssen Pharmaceutica. C.K.M. receives research support from Gilead Sciences, Merck, ViiV Healthcare and Janssen Pharmaceutica, is on the speaker’s bureau for Gilead Sciences, Merck and Insmed, and is on an advisory board for Gilead Sciences. E.S.D. receives research support from Gilead Sciences, Merck and ViiV Healthcare, and has served as a consultant for Gilead Sciences.
Peer review information Nature thanks Daniel R. Kuritzkes, Kevan Shokat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Link, J.O., Rhee, M.S., Tse, W.C. et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature 584, 614–618 (2020). https://doi.org/10.1038/s41586-020-2443-1
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