Novel imaging approach offers insights into HIV’s lifecycle
Posted: 21 August 2017 | Dr Zara Kassam (Drug Target Review) | No comments yet
Scientists have used a novel live-cell fluorescent imaging system that has allowed them to identify individual particles associated with HIV…
A team of scientists have used a novel live-cell fluorescent imaging system that has allowed them for the first time to identify individual particles associated with HIV.
The researchers at Northwestern Medicine were able to monitor how the HIV capsid uncoats in the cell at the individual particle level. They demonstrated that uncoating leading to infection occurs early in the cytoplasm, around 30 minutes after cell fusion. The finding is just one example of novel discoveries about HIV that might now be possible with the imaging system.
“Being able to connect infectivity of individual particles and how they behave in the cell to infection — which is what we really care about — is going to have a big impact on the field,” said principal investigator Dr Thomas Hope, Professor of Cell and Molecular Biology “The system can now be used to resolve other controversies in HIV biology and to determine which potential targets for drug development are most relevant.”
The study has implications in the wider field of virology research as well.
“Theoretically, you could apply this technique to the study of any fluorescently-tagged virus,” explained first author Dr João Mamede, Post-Doctoral Fellow in Dr Hope’s laboratory.
In future projects, Dr Hope’s research team plans to continue to leverage the method to study infection in later stages of the HIV lifecycle.
“We want to understand all the details, from when the virus fuses, to the point where it integrates and starts to make new viruses, to the last phase,” explained Dr Hope, “We need to understand what’s going on, so we can find the Achilles’ heel of the virus and use it as a drug target.”
The findings, published in Proceedings of the National Academy of Sciences, could help lead to the development of novel therapies for HIV prevention and treatment by providing a deeper understanding of the mechanisms of HIV’s lifecycle.
It has become routine to visualise the movement and progression of individual virions in cells, but the relevance of these observations was previously unclear, as many virions are defective or do not progress to make further copies of themselves.
“This approach — and the ability to say ‘that virion infected that cell’ — will help bring clarity to the field,” said Dr Hope. “It allows us to understand what the virus really needs to do to infect a cell. It gives us new details, like where in the cell it happens and the timing of specific events. The more we know about the virus, the better our chances are to stop it.”
During the course of infection, HIV fuses onto a target immune cell and delivers its capsid — a cone that holds the genetic material of the virus — into the cell’s cytoplasm. From there, the capsid disassembles through a process called “uncoating,” which is crucial to the synthesis of viral DNA from its RNA genome and the hijacking of the cell’s functions.
But the specific details of uncoating have been controversial, with two groups of thought. One believed that uncoating takes place late at pores, allowing factors to enter the nucleus. A second camp showed data suggesting that uncoating takes place early and in the cytoplasm.
Analysis, Antiretroviral Therapies, Drug Targets, Imaging
Dr João Mamede, Dr Thomas Hope