The objectives of this grant proposal are to determine the reasons why the uninfected T cells of HIV-1 (AIDS) infected individuals do not respond the uninfected T cells of HIV-1 (AIDS) infected individuals do not respond appropriately to stimulation by antigens. These defects in T cell function Or likely contribute to the nature of the opportunistic infections seen in AIDS, and therefore play an important part in the events that cause death in this infectious disease. Our hypothesis is that T cells are downregulated (or rendered refractory) by exposure to the HIV-1 envelope protein gp1120, even if active infection of the T cell does not occur. The basis for this hypothesis comes from the information that the gp120 receptor CD4 is intimately tied to T cell responsiveness to antigen, that stimulation of CD4 with Mab causes the T cell to be refractory to subsequent antigen stimulation, that soluble gp120 has recently been shown to cause similar down regulation, and finally that soluble gp120 can activate the T cell independent of antigen possibly causing a refractory period. Specifically, in this grant we will determine the mechanism by which gp120 either in soluble form or as part of whole virus down regulates the T cell, by measuring the T cells ability to generate antigen receptor dependent second messenger systems. The effects of gp120 on the subsequent activation of the TcR G protein, inositol phosphate metabolism and intracellular calcium will all be determined. These experiments have a direct relationship to the mechanism of the T cell immune defect seen in AIDs. When we completely understand the scope of this defect, we should be able to construct specific therapies to reverse them to help prevent the life threatening opportunistic infections of AIDs, while awaiting the development of effective anti- viral agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028736-04
Application #
3143263
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-09-30
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118