Imaging Techniques Reveal that HIV Infects
Host Cells Using a Molecular Entry Claw
An advanced imaging technique known as electron tomography has
allowed researchers at the National Cancer Institute (NCI), part
of the National Institutes of Health (NIH), to visualize an “entry
claw,” a unique structure formed between the human immunodeficiency
virus (HIV) that causes AIDS and the cell it infects. The findings
are in the May 4, 2007, issue of PLoS Pathogens.
“Visualizing the molecular mechanisms by which HIV and related
viruses enter their host cells can potentially lead to the identification
of novel drugs,” said NIH Director Elias A. Zerhouni, M.D.
Retroviruses such as HIV establish contact and enter their target
cells via an interaction between proteins on the surface of the
virus (called spikes) and specific host cell membrane receptors.
Previous studies have suggested that several spikes and several
cell receptors are involved in every virus infection event. The
findings of the NCI research team, led by Sriram Subramaniam, Ph.D.,
Laboratory of Cell Biology at NCI’s Center for Cancer Research,
demonstrate that this is true, but in a surprising way.
“This elegant research not only gives us insights into how HIV
and related viruses interact with proteins on the surface of cells
and then enter the host cells to integrate their DNA, it also gives
us important clues as to how to design improved anti-HIV therapy,” said
NCI Director John E. Niederhuber, M.D. “Electron tomography and
other new tools for imaging at the single-cell or subcellular level
also have the potential to help us actually see the subcellular
effects of many different diseases — including cancer — that
we could only guess at previously.”
In this study, the scientists showed that the interaction actually
takes the form of a tight cluster of five to seven rod-shaped features.
This striking and unexpected arrangement was dubbed the “entry
claw” by the researchers (see figure below). They also found that
the arrangement of spikes across the rest of the virus seems to
largely disappear upon formation of the entry claw, suggesting
a shedding event that has not previously been noted, which may
have some, still uncertain relevance to infectivity.
“The discovery of the entry claw raises many fundamental questions
about viral entry into host cells,” said Subramaniam. “What are
its precise molecular components? How does the viral genetic core
actually transfer to the host cell? What are the other intermediate
steps of the entry claw formation and can they be visualized? As
we continue to improve the technology, we believe we will answer
these and other related questions.”
Traditional imaging techniques based on light microscopy do not
offer sufficient resolution to see how cellular molecules and small
structures interact in actual life, and powerful techniques such
as X-ray crystallography can only define the structure of an individual
molecule or simple molecular interactions. Electron tomography
and related methods for 3D electron microscopy can fill this imaging
gap and reveal fine subcellular structures or virus-host interactions
in great detail. The Subramaniam lab has been pioneering advances
in 3D electron microscopy, and is applying the emerging technologies
to understanding not only virus-host interactions, but also visualizing
such things as structures inside the cell that distinguish cancer
cells from normal cells.
|Contact of HIV-1 with
T-cells. Electron tomographic analysis (left) reveals the
architecture of the virus-cell contact region which forms
an “entry claw” as shown in the schematic (right). Scale
bar in left panel is 100 nanometers wide.
For more information on this work and the Subramaniam laboratory’s
work in high resolution electron microscopy, go to http://hrem.nci.nih.gov.
For more information about cancer, please visit the NCI website
at http://www.cancer.gov, or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Reference: Sougrat R, Bartesaghi A, Lifson JD, Bennett
AD, Bess J, Zabransky DJ, Subramaniam S. Electron tomography of the contact
between T-cells and SIV/HIV-1: Implications for viral entry. PLoS Pathogens.
May 4, 2007.