Oral Presentation The 35th Biennial Conference of the Society of Crystallographers in Australia and New Zealand 2024 (Crystal 35)

Therapeutic Targeting of Retroviral Capsids: How Crystallography Found the Vulnerability in HIV's Armour (110058)

David A Jacques 1
  1. UNSW, UNSW Sydney, NSW, Australia

The two known human retroviruses are responsible for devastating diseases. Human Immunodeficiency Virus (HIV) has very poor survivability if left untreated, while Human T-Lymphotropic Virus (HTLV) is arguably the most potent carcinogen known, resulting in aggressive untreatable cancers. Whilst the retroviruses (especially HIV) are amongst the most studied human pathogens, there remain many underappreciated aspects of their lifecycles. One such aspect is the capsid – the protein 'shell' required to chaperone the viral genome across the cell to the nucleus. In this talk I will discuss the advances we have made in understanding the role of the HIV capsid highlighting its functions as: a shield for the genome, an adaptor for motor proteins, a deceiver of innate immune responses, a mimic of karyopherins, a determinant of pandemicity, and the target of the most potent antiretroviral drug ever developed. While HIV has been a great success story of modern medicine and antiviral drug development, HTLV has no available therapies. Around the world, HTLV is often a virus of neglected communities. In Australia, certain Indigenous communities have the highest rates of HTLV in the world. There is an urgent need for treatments for this virus, and I will show some recent breakthrough discoveries we have made regarding the HTLV capsid and its potential as a drug target.

  1. Dickson CF; Hertel S; Tuckwell AJ; Li N; Ruan J; Al-Izzi SC; Ariotti N; Sierecki E; Gambin Y; Morris RG; Towers GJ; Böcking T, Jacques DA*. The HIV capsid mimics karyopherin engagement of FG-nucleoporins. Nature 2024, 626, 836-842
  2. Zuliani-Alvarez L; Govasli ML; Rasaiyaah J; Monit C; Perry SO; Sumner RP; McAlpine-Scott S; Dickson C; Rifat Faysal KM; Hilditch L; Miles RJ; Bibollet-Ruche F; Hahn BH; Böcking T; Pinotsis N; James LC; Jacques DA*; Towers GJ*. Evasion of cGAS and TRIM5 defines pandemic HIV. Nature Microbiology 2022, 7, 1762-1776
  3. Price, A. J.; Jacques, D. A.; McEwan, W. A.; Fletcher, A. J.; Essig, S.; Chin, J. W.; Halambage, U. D.; Aiken, C.; James, L. C. Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly. PLoS Pathogens 2014, 10