Recent reports demonstrate that individuals lacking a functional CCR-5 chemokine receptor gene are resistant to infection with HIV-1 as CCR-5 is the coreceptor for macrophage-tropic HIV-1 (the most prevalent phenotype of transmitted HIV). The possibility of using chemokines therapeutically to block infection is being explored by a number of laboratories. However, the use of bioactive chemokines and the uncertain levels of expression that would have to be obtained are drawbacks to this approach. Therefore, the applicant seeks an alternative approach. The Principal Investigator s laboratory has demonstrated that lymphocytes expressing an intrakine (ER-retained chemokine, MIP-1a or RANTES) blocks cell surface expression of the CCR-5, and renders these cells resistant to infection with macrophage-tropic HIV-1. The goal of this proposal is to explore the potential use of """"""""intrakines"""""""" in human gene therapy. Murine retroviral vectors and packaging cell lines will be developed and transduction procedures established. Recombinant retroviruses will be tested for the ability to block HIV infection in primary human lymphocytes. In addition, myelomonocytic cells derived by transduction of human CD34+ stem cells will be assessed for resistance to macrophage-tropic HIV-1. Stromal cell-derived factor 1 (SDF-1) which can inactivate the T cell-tropic coreceptor CXCR4 will also be tested in primary lymphocytes and stem cells with the goal that co-expression of both intrakines may block both T cell and macrophage-tropic viruses. Potential toxicity will be assessed in a mouse model following the introduction of transduced progenitor cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI041959-01
Application #
2431634
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1997-09-01
Project End
2000-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biology
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106