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PROJECT
SUMMARY
UPDATE:
Sandra moved up to SanFran and eats rice-a-roni daily as a
proud rep. for Thermo-Fisher! We miss her dearly....
As a
member of the lentiviral family of retroviruses, HIV primarily
infects T-cells and macrophages. Viral entry is first mediated
through the binding of the viral envelope to two cellular
receptors, CD4 and coreceptor (CCR5 and/or CXCR4). These interactions
induce conformational changes within the viral envelope, thereby
leading to fusion of the viral and host membranes and transfer
of the viral genome into the target cell.
Dendritic cell specific ICAM-3 grabbing
nonintegrin (DC-SIGN) is a calcium dependent lectin that can
also bind to the viral envelope gp120. Primarily expressed
on dendritic cells (DCs), DC-SIGN binds to gp120 with greater
affinity than CD4. This high affinity interaction may play
a role in enhancing infection of cells in -trans and
-cis. Infection in -trans would involve the
binding of HIV by dendritic cells in the periphery, via DC-SIGN,
with its subsequent transfer to T cells in secondary lymphoid
organs, whereas DC-SIGN facilitated infection in -cis
would address cells that express DC-SIGN, along with CD4 and
coreceptor. In both cases, a threshold number of CD4 and coreceptor
must be expressed on target cells in order to achieve viable
infections. By using a double inducible cell line for CD4
and CCR5, we will be able to control expression levels for
each receptor and examine whether DC-SIGN facilitated infection
in -trans or -cis will decrease these quantitative
requirements on target cells. These phenomena would have implications
for the establishment of viral reservoirs and expanding viral
tropism.
We will also be infecting these
double inducible cells with different viral isolates to determine
whether pathogenicity is associated with coreceptor dependence
at the level of entry and how this will then translate into
other parts of the viral life cycle.
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