1. Kinetics of HIV-1 capsid uncoating revealed by single-molecule analysis
- Author
-
David A. Jacques, Vaibhav Shah, Conall McGuinness, Andrew Wong, Stuart Turville, Chantal L. Márquez, James C. Walsh, Derrick Lau, Anupriya Aggarwal, Till Böcking, and Michael W. Parker
- Subjects
0301 basic medicine ,QH301-705.5 ,Science ,viruses ,Protein subunit ,030106 microbiology ,Plasma protein binding ,General Biochemistry, Genetics and Molecular Biology ,Virus ,03 medical and health sciences ,Biology (General) ,General Immunology and Microbiology ,Chemistry ,General Neuroscience ,HEK 293 cells ,capsid disassembly ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Virology ,Small molecule ,Reverse transcriptase ,3. Good health ,030104 developmental biology ,Capsid ,Structural biology ,HIV-1 ,fluorescence miscoscopy ,Medicine ,single-molecule - Abstract
Viruses need to enter their host’s cells in order to replicate their genetic material and produce more copies of the virus. A protein shell called a capsid protects the virus during this journey. But the structure of the capsid presents a mystery. How can this protein shell be strong enough to remain intact as it enters a host cell, and yet quickly open up to release the viral genome after replication? Unlike the capsids of many other viruses, those of HIV have irregular structures that rapidly fall apart once removed from the virus. This has thwarted attempts to study intact HIV capsids in order to understand how they work. However, we do know that HIV hijacks a range of molecules produced by the invaded host cell. Dissecting their effects on the capsid is key to understanding how the capsid disassembles. Marquez et al. have now developed a method that can visualize individual HIV capsids – and how they disassemble – in real time using single-molecule microscopy. This revealed that capsids differ widely in their stability. The shell remains closed for a variable period of time and then collapses catastrophically as soon as it loses its first subunit. Using the new technique, Marquez et al. also found that a small molecule drug called PF74 causes the capsid to crack open rapidly, but the remaining shell is then stabilized against further disassembly. These observations reconcile seemingly contradictory observations made by different research groups about how this drug affects the stability of the capsid. The method developed by Marquez et al. enables researchers to measure how molecules produced by host cells interact with the viral capsid, a structure that is fundamental for the virus to establish an infection. It could also be used to test the effects of antiviral drugs that have been designed to target the capsid. The new technique has already been instrumental in related research by Mallery et al., which identifies a molecule found in host cells that stabilizes the capsid of HIV.
- Published
- 2018