Immune-based therapy approaches that directly inhibit viral replication through activation of MHC-restricted mechanisms such as CD8+T cell effector function remain an area of active investigation. Here we propose to investigate a novel approach based on antiviral activity of a MHC non-restricted human cytotoxic T cell line, TALL-104 (CD3/TCR+ CD8+ CD56+ CD16-). TALL-104 cells are cytotoxic in vitro against a broad range of tumors across several species, without lysing cells from normal tissues. Importantly, TALL-104 cells have already been extensively characterized as an adoptive cell therapy in pre-clinical studies (over 10 years) including FDA approved phase I/II human clinical trials for the treatment of cancer patients. Our preliminary data in HIV-infected cultures show that TALL-104 cells can inhibit viral replication and kill HIV-infected cell in vitro. An increase in TALL-104 mediated killing of chronically infected lines ACH-1 and U1 was associated with HIV replication in these cells. Based on additional preliminary data documenting viral suppression of chronically infected T cells, we propose to test the hypothesis that TALL-104 cells can inhibit HIV-1 in primary lymphocytes and macrophages through activation of non-MCH-restricted mechanisms including direct cytotoxicity and secretion of antiviral soluble factors. In order to test our hypothesis, we will evaluate: 1. Analyze the antiviral activity of TALL-104 cells in primary cells, and more specifically: a) The activity of TALL-104 cells in decreasing viral replication in in vitro acutely infected X4 and R5 primary CD8-depleted T cells and monocyte-derived macrophages (MDM). b) The ability of TALL-104 cells to inhibit activation-induced viral replication in cells from HIV-1 infected patients. 2. Define the mechanisms involved in the anti-HIV activity by TALL-104 cells by: a) Analysis of the role of activating cytotoxic receptors (NCRs) NKp46 and NKG2D involved in triggering the killing HIV-infected. b) Analyzing the cytotoxic mechanisms responsible for killing HIV-infected cells: cytotoxic factors (granzymes and perforin) and cytotoxic mediators (Fas-L and tumor necrosis factor-related apoptosis-inducing ligand-TRAIL). c) Defining the role of potential soluble factors in the inhibition of viral replication (RANTES, MIP-1alpha, MIP-1beta and SDF-1). The work proposed represents a collaboration between The Wistar Institute, The University of Pennsylvania, Philadelphia FIGHT (Jonathan Lax Treatment Center).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI058780-01A1
Application #
6843334
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Voulgaropoulou, Frosso
Project Start
2004-09-30
Project End
2006-08-31
Budget Start
2004-09-30
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$187,684
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104