HIV gene causes formation of nuclear herniations halting cell division, Gladstone researchers find

Peering into the fascinating world of HIV biology, researchers at the Gladstone
Institute of Virology and Immunology have found that an HIV gene called Vpr
causes the membrane surrounding the nucleus-the nuclear envelope-to form
herniations that project and retract much like solar flares radiating from the
surface of the sun.

Intermittently, these Vpr-induced herniations rupture leading to the
inappropriate mixing of cellular components that are normally carefully
separated between the nucleus and surrounding cytoplasm. This observation is
giving clues to how Vpr helps HIV to take over a cell in its effort to conquer
an entire immune system.

The study will be published in the Nov. 2 issue of the journal Science.

“We would have not detected these remarkable changes in nuclear envelope
structure induced by Vpr if we had not turned to time lapse video microscopy
that permits analysis of a single cell over time,” said Warner Greene, MD, PhD,
senior co-author, director of the Gladstone Institute of Virology and
Immunology, and UCSF professor of medicine, microbiology, and immunology.

Vpr produces these dynamic changes in nuclear architecture by altering the
highly ordered structure of a family of proteins termed the nuclear lamins. 
The lamins form a supporting network of filaments that line the inner surface
of the nuclear envelope. “In the presence of Vpr, the structure of the nuclear
lamins becomes disorganized,” said lead author Carlos de Noronha, PhD, a
research scientist at Gladstone.  These changes combine to disable the cell
from carrying out vital functions including cell division.

Inhibiting cell division is important to HIV’s cell-conquering strategy.
Without cell division, virus production increases by severalfold, greatly
improving HIV’s ability to grow. “Then HIV can infect more new target cells
leading to faster spread of the infection,” de Noronha said.

The Gladstone research team captured the images by attaching a green or red
fluorescent dye to various proteins that govern how the cell divides. One of
these proteins is Wee1. During a normal cell cycle, the fluorescent-tagged Wee1
remains confined to the cell nucleus until minutes before cell division
occurs.  However, in the presence of Vpr, the time lapse videos revealed the
transient formation of nuclear herniations containing Wee1 and Vpr that
intermittently burst allowing Wee1 and other nuclear proteins to flood into the
cytoplasm.

Similarly, cytoplasmic proteins spilled into the nucleus through the newly
formed rupture in the nuclear envelope.  These intracellular events combine to
halt cell division.  “These experiments have provided us with an entirely new
perspective on how HIV impairs the progression of cells through the normal cell
cycle,” Greene said.

Other co-authors include Michael P. Sherman, MD, PhD, Gladstone research
scientist; Harrison W. Lin, BA, Gladstone research associate; and Marielle
Cavrois, PhD, Gladstone postdoctoral fellow. Other co-authors are Robert D.
Goldman, PhD, Stephen Walter Ranson professor and chair of cell and molecular
biology; and Robert D. Moir, PhD, research associate professor of cell and
molecular biology at Northwestern University Medical School.

The study was funded by the National Institutes of Health and the UCSF-GIVI
Center for AIDS Research.

The Gladstone Institute of Virology and Immunology is one of three research
institutes that comprise the J. David Gladstone Institutes, a private
biomedical research institution affiliated with the University of California,
San Francisco. The institutes are named for a prominent real estate developer
who died in 1971. His will created a testamentary trust that reflects his
long-standing personal interest in medical education and research.

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