Structure of HIV outer shell determined
31 Jan 2011
The structure of the protein package that delivers the genetic
material of the human immunodeficiency virus (HIV) to human cells has
been mapped by the The Scripps Research Institute and the University of
The work is the culmination of studies carried out over the last
decade looking at different portions of the capsid — the cone-shaped
container, of the virus.
The final piece of the puzzle, described in an article published
in the journal Nature on January 20, 2011, details the
structure of the two ends of the cone.
“This paper is a real milestone for research from our group,”
says the study’s senior author Mark Yeager, M.D., Ph.D., a Scripps
Research professor and staff cardiologist and chair of the Molecular
Physiology and Biological Physics Department at The University of
Virginia School of Medicine.
A detailed description of the complete HIV capsid will provide a
roadmap for developing drugs that can disrupt its formation and thus
prevent infection by HIV.
|The new detailed description of the
complete HIV capsid.
The capsid of HIV is a conical
fullerene shell that comprises about 250 hexamers (orange)
and exactly 12 pentamers (gold) of the viral CA protein. In
the new study, the researchers determined X-ray crystal
structures of these building blocks, which enabled modeling
of the complete capsid at atomic resolution.
continuously varying lattice curvature in the fullerene cone
can be explained simply by two rigid body rotations around
two assembly interfaces of CA. (Graphics by Owen Pornillos, Barbie Ganser-Pornillos, Kelly Dryden, and
Assembling the package
HIV binds to receptors on human cells and then delivers the
capsid inside them. Once inside a cell, the capsid comes apart,
releasing its precious cargo — the virus’s genetic material.
HIV then sabotages the cell machinery to make many copies of its
genes and proteins. As new viruses are made, the genetic material is
packaged into spherical immature capsids that HIV uses to escape
from the infected cell. But before these newly released viruses can
infect other cells, the immature capsid undergoes a dramatic
rearrangement to form the mature, cone-shaped shell.
If formation of the mature capsid is disrupted, the virus is no
longer infectious. Thus, new drugs targeting capsid formation could
provide valuable additions to the arsenal of existing drugs against
A "floppy" bridge
To develop drugs that disrupt capsid formation, however,
scientists first need to know precisely how it is formed. One
technology researchers use to obtain detailed structures of
biological molecules is X-ray crystallography. This technique
requires growing crystals of a molecule and then bombarding the
crystals with X-rays to determine the positions of all the atoms.
But unlike the cone-shaped capsids of other viruses, such as the
poliovirus, which have a rigid, symmetrical structure that
obediently assembles into crystals, the HIV capsid is flexible and
can adopt slightly different shapes.
Part of the reason for this flexibility is the protein that makes
up the HIV capsid, the CA protein, consists of two ends held
together by a “floppy” bridge.
In the capsid, each CA protein joins hands with other CA
proteins, forming groups of five or six proteins. The main body of
the capsid contains about 250 of the six-fold units or hexamers.
Each end of the cone is then closed off by either five or seven
smaller five-fold units or pentamers.
“It is impossible to grow crystals of the entire HIV capsid,”
says Yeager. As a result, his team used a “divide and conquer
Divide and conquer
Working with husband-and-wife team Owen Pornillos and Barbie
Ganser-Pornillos, investigators in his lab, Yeager partitioned the
HIV capsid into smaller components, then determined their respective
Yeager's group started by focusing on the structure of the CA
hexamer. A breakthrough came in a 2007, when the group viewed the CA
hexamers with a powerful electron microscope. Guided by information
from that structure, in 2009 the team managed to trick the CA
hexamers into forming crystals. The researchers were then able to
determine the particles’ structures at 2-Angstrom resolution (one
Angstrom equals one ten-billionth of a meter).
Having cracked the atomic structure of the hexamer, the
investigators turned their attention to the more elusive pentamers.
Structure of the Pentamer
In this latest study, Yeager, Pornillos, and Ganser-Pornillos
used techniques similar to those they had applied to the hexamers to
obtain the crystal structures of the CA pentamers.
The new structure reveals that five CA proteins link hands at one
end, called the N-terminal domain (NTD), to form a circle. The
opposite ends of the CA proteins, called C-terminal domain (CTD),
form a floppy belt around this central core. Then, CTD links to CTD
to connect adjacent pentamers.
The structure reveals flexibility and mobility both between the
central core and belt within each pentamer and at the CTD-CTD
interfaces of adjacent pentamers. The CTD subunits can rotate
relative NTDs. “As a result, each ring can adopt slightly different
angles relative to its adjacent rings,” says Pornillos, first author
of the paper.
The structure of the pentamers is remarkably similar to that of
the hexamers, notes Pornillos, with one important difference.
Because pentamers are smaller than hexamers, the amino acids, the
building blocks of proteins, at the center of the pentamer ring are
closer together than in the hexamer.
Many amino acids have positive or negative charges. When two
amino acids with the same charge are close together they tend to
push each other away. One amino acid in the CA protein, called
arginine, with a positive charge, sits smack in the middle of both
the hexamer and pentamer ring.
Because in the pentamer the arginines are packed much closer
together, they repel one another, making the pentamer a less stable
structure than the hexamer. This may explain why there are many more
hexamers in the mature HIV capsid compared to pentamers.
The only place where pentamers are likely to form is at the
capsids’ ends, where the linked CA proteins have to bend
dramatically to close off the capsid—a feat the pentamer is more apt
“Arginine is the critical switch between hexamer and pentamer
formation,” says Yeager. “We can finally explain why the CA protein
would make one or the other.”
An atomic model of the HIV Capsid
Having solved the atomic structures of both CA hexamers and
pentamers, Yeager and colleagues for the first time were able to
build a complete atomic model of the mature HIV capsid.
The researchers now plan to further refine the model using
sophisticated computer programs to determine the stability of the
structure in different regions and to identify possible “weak”
points they can target using newly designed drugs.
They will also begin studying the structure of the immature
capsid to determine how this version of the capsid transitions to
the mature form — a step in the virus lifecycle that has remained
“We don’t have the full story yet, but we have volume one,” says
Owen Pornillos, Barbie K. Ganser-Pornillos, Mark Yeager. Atomic
level modeling of the HIV capsid. Nature, January 20, 2011.