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Viral Envelopes: Structure-Function Studies
Monday, 1:30 - 3:30 pm
Background: The membrane fusion events that initiate HIV-1 infection and promote cytopathic syncytium formation in infected cells commence with the binding of HIV envelope glycoprotein (Env) to CD4 and an appropriate co-receptor. The currently accepted model of syncytium formation suggests that HIV-induced cell fusion is independent of signaling stimulated by ligation of CD4 or coreceptor.
Results: Here, we show that HIV Env/co-receptor
interactions activate Rac-1 GTPase and stimulate actin filament network
reorganizations that are requisite components of the cell fusion process. Disrupting
actin filament dynamics with jasplakinolide or latrunculin A arrested fusion at
a late step occurring after formation of Env/CD4/co-receptor complexes. Time-lapse
confocal microscopy of living cells revealed vigorous activity of actin-based,
target cell membrane extensions at the target/Env-expressing cell interface.
Expression of dominant-negative forms of actin-regulating Rho-family GTPases
established that HIV Env-mediated syncytium formation relies on Rac-1, but not
Conclusions: These results suggest that G-protein-independent signaling events regulate HIV-induced cell fusion and define a role for HIV Env/coreceptor interactions in activating cellular factors essential for syncytium formation.
Keywords: HIV; cell-cell fusion; Rac-1 GTPase