EMD Millipore eBook - 11

Analyzing Cell Death * Defenders Against Death

The rare antibodies selected functioned by inhibiting the virus-encoded
protease that is necessary for viral maturation. cglightNing/Fotolia.com

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rhinovirus. Cells expressing functional antibodies were expected to be protected from
death while other cells were killed. The antibody-coding information from the surviving
cells was fed into a secondary lentiviral library that served as the starting point for
the next round of selection (see Figure on page 12). After five rounds of such selection,
the team obtained antibodies that when expressed in the cytoplasm as distinct
agents were shown to offer protection to mammalian cells from rhinovirus-induced
death. Mechanism of action studies implicated the viral 3C protease, responsible
for virus maturation, as the target to which the antibodies bound and whose
blockage rescued the mammalian host cell from virus-induced cell death.
The present work is a fine example of a selection strategy that carries an additional
kinetic-based component, as if the virus infection and host cell replication enter a race
of sorts during the initial stages of which any rare rescue antibody clones remain invisible
and are only revealed if they are truly effective and after several successive rounds of
enrichment. It is anticipated that future uses of this approach will incorporate earlier
markers for cell death, such as onset of apoptosis, autophagy, or cell cycle arrest. In
turn, knowing the factors that preferentially protect cells from death should inform
the efforts directed at finding ways to selectively kill unwanted cells, such as rapidly
proliferating cancers.
One of the most important phenotypes in biology is cell death. One way to probe the
mechanism(s) of cell death is to select molecules that prevent it and learn how this was
accomplished. Here, intracellular combinatorial antibody libraries were used to select
antibodies that protected cells from killing by rhinovirus infection. These rare antibodies
functioned by inhibiting the virus-encoded protease that is necessary for viral maturation.

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