Unexpected findings detailed in new portrait of HIV

Date:
February 16, 2022
Source:
University of Washington
Summary:
Using powerful tools and techniques developed in the field of
structural biology, researchers have discovered new details about
the human immunodeficiency virus, HIV.



FULL STORY ========================================================================== Using powerful tools and techniques developed in the field of structural biology, researchers at the University of Washington and The Scripps
Research Institute have discovered new details about the human
immunodeficiency virus, HIV. The findings bring into focus the basic architecture of the virus just above and below its surface and may help
in the design and development of a vaccine that can protect against AIDS.


========================================================================== These detailed findings include 3D views of the structure and position
of the virus' envelope "spike" proteins (the Env protein, used when the
virus binds with cells) in the context of the full virus. Normally,
researchers view the protein particles separated from the virus or
expressed as engineered or purified proteins. In another key development,
the scientists shed new light on the glycan shields -- the sugars on
the proteins that can hide it from the body's immune system.

"We're looking at the whole virus particle and how this protein on
the surface relates to the rest of the virus," said lead author Kelly
Lee, associate professor of medicinal chemistry in the UW School of
Pharmacy. "And by looking at the intact virus structure, we can see how
the different facets of this 'face of the virus' are being displayed
and how they would be recognized by or hidden from the immune system."
This intact view of the virus also allowed the scientists to gain new
insights into positioning of the envelope spike protein on the surface
relative to the internal protein structure, called the Gag lattice.

"This finding overturns previous models of how the parts of the viruses
are assembled and helps to focus our attention on where the docking
interaction of these two proteins is likely to be," Lee said. "This
interaction needs to be resolved in more detail, but at least the current
work gives us the correct architectural model for the virus assembly."
It was this particular finding that led to the title of the paper --
"Cryo-ET of Env on intact HIV virions reveals structural variations
and positioning on the Gag lattice" -- published Feb. 4 in the journal
Cell. Another finding that had not been previously observed, the
scientists pointed out, is that the "stalk" supporting the envelope
proteins is flexible and can tilt, presenting both opportunity and
challenges to the immune system's neutralizing antibodies that protect
cells from infection.

"Structural biology has driven HIV vaccine design, so as we get a better
and better picture of what it is we're targeting, that inspires innovation
and may lead to improved vaccines," said co-corresponding author Michael
Zwick, associate professor of immunology and microbiology at the Scripps Research Institute.

HIV's envelope presents a particularly difficult target for vaccine development, Zwick added, because the virus displays so few spikes and camouflages them with sugar molecules so as to evade our immune system.

"All these features increase the dynamic variability that the HIV spike
protein presents to the immune system," said Lee, who also directs a UW
lab exploring virus structure and dynamics. "This is something that people
in HIV vaccine development have grappled with from the very beginning --
this virus mutates and changes itself astronomically and rapidly. Each
time it infects an individual, you end up with literally thousands of
different variants within that one individual, and if you look across populations, it's multiplied even more." In fact, in February, an even
more deadly strain of HIV was found to have been circulating in the Netherlands. Luckily, while the strain is a "highly virulent variant,"
it still responds to treatment.

"This is just another reminder that these viruses are always changing,
so we need scientists to continue studying them," Zwick said.

Co-authors are Vidya Mangala Prasad, former acting instructor at UW School
of Pharmacy, currently at the Indian Institute of Science; Daniel Leaman, Department of Immunology and Microbiology, The Scripps Research Institute; Klaus Lovendahl, Jacob Croft and Edgar Hodge, Department of Medicinal Chemistry, UW School of Pharmacy; and Mark Benhaim, who worked on the
project as a graduate student at UW.

========================================================================== Story Source: Materials provided by University_of_Washington. Original
written by Jake Ellison. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Vidya Mangala Prasad, Daniel P. Leaman, Klaus N. Lovendahl, Jacob T.

Croft, Mark A. Benhaim, Edgar A. Hodge, Michael B. Zwick, Kelly
K. Lee.

Cryo-ET of Env on intact HIV virions reveals structural variation
and positioning on the Gag lattice. Cell, 2022; DOI: 10.1016/
j.cell.2022.01.013 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220216153905.htm

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