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Principal Investigator:
Dan R. Littman, M.D., Ph.D.,
Skirball Institute of Biomolecular Medicine
and the Department of Microbiology and Pathology
Howard Hughes Medical Institute Investigator,
New York University School of Medicine
Background
AIDS virus (HIV) infects cells of the immune system by sequentially interacting
with two different receptors on the cell surface. The first is CD4 to which the
virus binds tightly, and which allows the binding to a second, lower affinity
receptor. Several molecules, all of which are members of a chemokine receptor
family, have been identified as these second receptors (at least eleven chemokine
receptors have been identified, some of which are "orphans" whose function is
unknown). The interaction with chemokine receptors triggers the fusion of viral
and cellular membranes, facilitating viral entry into the cell. Since viral binding
to chemokine receptors is an essential step in HIV pathogenesis, blocking this
interaction would inhibit HIV infection.
Description of Project
Dr. Dan Littman has developed a novel assay to identify inhibitors of chemokine
receptors. The most important chemokine receptors for HIV infection are CCR5 and
CXCR4. During early stages of HIV infection, viruses express glycoproteins on
their surface with specificity for CCR5. At later times during the disease, viruses
express CXCR4 specific glycoproteins on their surfaces. Strains of HIV isolated
late in disease progression also have envelope glycoproteins that can interact
with a number of chemokine receptors other than CCR5 and CXCR4. Thus, the virus
may be able to mutate and change its specificity for a particular chemokine receptor.
The ability of HIV strains to bind several different chemokine receptors adds
complexity in targeting this step for drug development. One means to address this
problem is to isolate inhibitors for all known chemokine receptors.
Dr. Littman's assay enables the isolation
of inhibitors to various chemokine receptors. It consists of replication
defective viruses, which encode a reporter molecule consisting of various
envelope glycoproteins, with affinity for different chemokine receptors.
When this virus infects its target cell and integrates into the host genome,
the reporter gene will get expressed, allowing for a rapid quantitation of
infection. Libraries of compounds can then be screened on the basis of their
ability to block infection of cells that express CD4 and the relevant coreceptor.
Non-specific blockers can be easily screened out by testing whether they
also block viral entry through another chemokine receptor, or through receptors
for murine viruses.
Applications
The chief application of this technology is high throughput
screening for small molecule inhibitors of HIV. Chemokine receptors
are also implicated in processes relevant to inflammatory disease.
Therefore, in addition to presenting a new target for anti-HIV
drug discovery, CCR-5 and other chemokine receptors may also be
attractive targets for the development of novel anti-inflammatory
drugs.
Patent Status
U.S. and foreign patent applications have been filed covering this novel assay
and its associated cell lines including a panel of human chemokine receptors (CCR1 &endash;
5, CXCR4, Bob and Bonzo).
For further information please contact
New York University
Industrial Liaison/Technology Transfer
650 First Avenue, New York, N.Y. 10016
Tel: (212)263-8178 Fax: (212)263-8189
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