Friday, 31 May 2019

New imaging reveals previously unseen vulnerabilities of HIV


Imagine that HIV is a sealed tin can: if you opened it, what would you find inside? An international team led by researchers at the University of Montreal Hospital Research Centre (CRCHUM), Tufts University School of Medicine, and the University of Melbourne think they know. Researchers have visualized what the "open can" of the human immunodeficiency virus looks like, revealing a previously unknown virus shape and a very detailed image of the vulnerabilities of the virus.

The breakthrough was made possible through the use of a molecular "can opener" to expose parts of the virus envelope that can be targeted by antibodies.

The characterization of the new shape of the virus envelope reveals unique details about the vulnerability of HIV that might be useful in strategies aimed at its eradication. This finding opens new paths in the fight against the virus.

When HIV infects cells of the human immune system, it uses its envelope's spike to attach itself to specific receptors on the cells, called CD4 and CCR5. Binding to the CD4 receptor triggers changes in the shape of the envelope that allow the virus to infect the host cell. The new research describes the use of small-molecule CD4-mimetic compounds designed and synthesized at the University of Pennsylvania to force the virus to open up and to expose vulnerable parts of its envelope, allowing the immune system cells to kill the infected cells.

In an earlier study published in PNAS in 2015, researchers led by Finzi showed that exposing these vulnerable parts of the envelope facilitates the elimination of infected cells by a mechanism known as antibody-dependent cellular cytotoxicity (ADCC).

Tufts researchers were able to visualize the previously unknown shape of the virus envelope using a new technology -- single-molecule Förster resonance energy transfer, or smFRET -- that allows researchers to see how distinct elements of the envelope move with respect to one another. This provides a direct means of seeing that the HIV envelope is a dynamic machine with moving parts that allows it to adopt various shapes in response to stimuli such as antibodies or small molecules.

See: An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity. Cell Host & Microbe, 2019; 25 (4): 578 DOI: 10.1016/j.chom.2019.03.002

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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