Accumulating data suggest that assembly and budding of different viruses, including HIV-1, takes place in glycosphingolipid and cholesterol enriched lipid rafts. Although a direct involvement of rafts in HIV-1 entry has not yet been presented, recent studies strongly suggest this possibility. Our preliminary results demonstrate that that HIV-1 entry into CD4+ T cells requires the presence of intact lipid rafts. This possibility was further substantiated by the observation that HIV-1 receptors, CD4, CXCR4, and CCR5, associate with lipid rafts. Since HIV-1 entry requires cooperation between multiple virus receptors, distribution of these receptors in different rafts may have important implications for the rate and efficiency of membrane fusion and HIV-1 entry. We hypothesize that effective raft aggregation is required to concentrate receptors locally to levels necessary for virus fusion and entry. Furthermore, we hypothesize that HIV-1 stimulates raft aggregation by inducing signaling upon binding to CD4 and/or coreceptors. In this proposal we will address the following issues:
in Specific Aim number 1, we will determine whether the association of HIV-1 receptors with lipid rafts and the integrity of rafts is required for HIV-1 entry into CD4+ T lymphocytes. This will be achieved by analyzing how modification or disruption of rafts affects virus entry.
In Specific Aim number 2, we will investigate the distribution of HIV-1 receptors in lipid rafts. We hypothesize that receptors used by HIV-1 may be distributed non-randomly in different raft populations.
In Specific Aim number 3, we will elucidate the molecular mechanism(s) targeting CD4 receptors into lipid rafts. We believe that HIV-1 entry may be inhibited by preventing localization of the CD4 receptors to lipid rafts. Finally, in Specific Aim number 4, we will examine the molecular mechanism(s) of HIV-1-induced raft aggregation paying special attention to the role of HIV-1-induced signaling in this process. We believe that this study will provide a rational basis for a new therapeutic approach to interfere with HIV-1 entry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI050461-01A1
Application #
6450420
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Wassef, Nabila M
Project Start
2002-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
1
Fiscal Year
2002
Total Cost
$102,188
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218