Although HIV infected individuals generate a large number of antigen-specific CD8 T cells, they are unable to control the virus and eventually develop clinical AIDS. We, and others have shown that freshly isolated HIV-specific CD8 T cells are functionally impaired. Further preliminary results suggest that HIV-specific T cells but not CMV-specific T cells from the same infected individual exhibit phenotypic features of immaturity. One striking phenotypic difference between HIV-specific CD8 T cells from CD8 T cells responding to other well-controlled chronic viruses such as CMV, is the failure to downmodulate the TNF family costimulatory molecule CD27. CD27 downmodulation normally occurs after interaction with its ligand CD70, and this interaction appears to be critical for the terminal maturation of T cells and expression of the key cytotoxic molecule perforin. Thus, the underlying defect in HIV infection may be a failure to express CD70, resulting in the failure to generate CD27 triggered costimulatory signals. To test this hypothesis, in Aim 1, we will investigate whether providing CD70 exogenously restores or enhances proliferation, cytotoxicity and IFN-gamma secretion of HIV-specific CD8 T cells. As EBV-transformed B lymphoblastoid cell lines (BLCLs) express CD70 abundantly, we will first test if blockade/abrogation of the molecule on autologous BLCLs diminishes their ability to stimulate HIV-specific CTL. We will also provide CD70 exogenously in soluble form or by lentiviral delivery during ex vivo culture of the cells with and without antigen stimulation, and test their ability to kill HIV-infected and peptide-pulsed targets and to produce cytokines. Because a small subpopulation of HIV-infected individuals, the long-term nonprogressors are able to control the virus in the absence of treatment, in the second specific aim, we will examine whether an intact CD70 costimulation pathway is responsible for maintenance of a functional virus-specific CD8 T cells in these subjects. We will block CD27/CD70 interactions during ex vivo stimulation using blocking antibody, CD27Ig chimera and RNAi and test if this treatment diminishes their responsiveness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI065342-01A1
Application #
7006797
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Li, Yen
Project Start
2005-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$283,500
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
Ranjbar, Shahin; Tsytsykova, Alla V; Lee, Sang-Kyung et al. (2006) NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site. PLoS Pathog 2:e130