Specific Roles for Lipids in Virus Fusion and Exit Examples from the Alphaviruses - Fusion of Biological Membranes and Related Problems - page 438

on cell-cell fusion must be validated using direct infection and/or fusion
assays.
in vivo work using mice genetically resistant to infection showed that
a hypercholesterolemic diet can make mice susceptible to MHV infection
(an effect reversible with a normal diet) and that hepatocytes isolated from
these hypercholesterolemic animals have increased virus adsorption and
intracellular titer versus control animals (Braunwald et al., 1991). To address
the issue of whether or not this enhancement is due to changes in mem-
brane fluidity, the genetically resistant A/J mice were fed one of two
diets, either a hypercholesterolemic (HC) or a phosphatidylserine (PS) diet
(Nonnenmacher et al., 1994). The expected result is that the cholesterol
would decrease membrane fluidity, while the PS would increase membrane
fluidity. The HC diet increases hepatocyte susceptibility to MHV infection
about 5 fold, while the PS diet has a significant dose-dependent inhibition.
However, when fluorescence anisotropy measurements were performed on
the cultured hepatocytes from these animals to characterize membrane flu-
idity, both the HC and PS diets produce an increase in fluidity, indicating
that there is no correlation between fluidity and infection. These results
are consistent with work by others showing that HC diets can be at least
partially compensated by cellular homeostatic mechanisms, which tightly
regulate the effects of increased dietary cholesterol on membrane fluidity
(Larsen et al., 1993). Taken together, these results suggest that cholesterol
could play a role in both the initial MHV binding/fusion steps and the later
stages of virus-induced cell-cell fusion. More work is necessary to fully
understand the role of cholesterol in the lifecycle of MHV, but it is intrigu-
ing that dietary components may be able to modulate the genetically-
determined susceptibility to virus infection.
6.2.3. Ebola Virus
Ebola virus is a member of the Filoviridae, filamentous enveloped
RNA viruses that can cause severe hemorrhagic disease in humans. Similar
to the work described earlier for HIV, recent work has focused on liposome
fusion induced by the putative fusion peptide of the Ebola virus glycopro-
tein (Ruiz-Arguello et al., 1998). The ability of synthetic peptides corre-
sponding in sequence to the putative fusion peptide to induce fusion of
liposomes is strictly dependent on the presence of Ca 2+ in the reaction and
phosphatidylinositol (PI) in the vesicle membranes. In fact, the best fusion
rate and efficiency are achieved using large unilamellar vesicles with a lipid
composition approximating that of the hepatocyte plasma membrane
(PC : PE : Chol. : PI 2 : 1 : 1 : 0.5). The effect of PI is at least partially mediated
by the initial interaction of the peptide and liposomes, but appears not to