CC Chemokine Receptor 5 DNA, New Animal Models and Therapeutic Agents for HIV Infection


Chemokine receptors are expressed by many cells, including lymphoid cells, and function to mediate cell trafficking and localization. CC chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled receptor (GPCR) which regulates trafficking and effector functions of memory/effector T-lymphocytes, macrophages, and immature dendritic cells. Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways. Like many other GPCRs, CCR5 is regulated by agonist-dependent processes which involve G protein coupled receptor kinase (GRK)-dependent phosphorylation, beta-arrestin-mediated desensitization and internalization.

Human CCR5 also functions as the main coreceptor for the fusion and entry of many strains of human immunodeficiency virus (HIV-1, HIV-2). HIV-1 transmission almost invariably involves such CCR5-specific variants (designated R5); individuals lacking functional CCR5 (by virtue of homozygosity for a defective CCR5 allele) are almost completely resistant to HIV-1 infection. Specific blocking of CCR5 (e.g. with chemokine ligands, anti-CCR5 antibodies, CCR5-blocking low MW inhibitors, etc.) inhibits entry/infection of target cells by R5 HIV strains. Cells expressing CCR5 and CD4 are useful for screening for agents that inhibit HIV by binding to CCR5. Such agents represent potential new approaches to block HIV transmission and to treat infected people. A small animal expressing both human CCR5 along with human CD4 supports entry of HIV into target cells, a necessary hurdle that must be overcome for development of a small animal model (e.g. transgenic mouse, rat, rabbit, mink) to study HIV infection and its inhibition.

The invention embodies the CCR5 genetic sequence, cell lines and transgenic animals, the cells of which coexpress human CD4 and CCR5, and which may represent valuable tools for the study of HIV infection and for screening anti-HIV agents. The invention also embodies anti-CCR5 agents that block HIV env-mediated membrane fusion associated with HIV entry into human CD4-positive target cells or between HIV-infected cells and uninfected human CD4-positive target cells.

Inventors:

Christophe Combadiere (NIAID)  ➽ more inventions...

Yu Feng (NIAID)  ➽ more inventions...

Edward Berger (NIAID)  ➽ more inventions...

Ghalib Alkhatib (NIAID)  ➽ more inventions...

Philip Murphy (NIAID)  ➽ more inventions...

Christopher Broder (NIAID)  ➽ more inventions...

Paul Kennedy (NIAID)  ➽ more inventions...


Intellectual Property:
U.S. Pat: 7,374,872 issued 2008-05-20
U.S. Pat: 8,198,042 issued 2012-06-12
U.S. Pat: 7,151,087 issued 2006-12-19
US Application No. 10/700,313
US Application No. 10/439,845
PCT Application No. PCT/US97/09586
US Application No. 08/864,458
US Application No. 60/018,508
US Application No. 13/012,482

Publications:
G Alkhatib et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955-1958. PubMed abs

Collaboration Opportunity:

The NIAID Laboratory of Molecular Immunology and Laboratory of Viral Diseases are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize CCR5-related products. Please contact Philip Murphy (301-496-8616, pmm@nih.gov) or Edward Berger (301-402-2481, edward_berger@nih.gov) for more information.


Licensing Contact:
Benjamin Hurley, Ph.D.
Email: benjamin.hurley@nih.gov
Phone: 240-669-5092

OTT Reference No: E-090-1996-0
Updated: Jun 1, 2007