Abstract

This is the final resubmission of an RO1 application from a new investigator aimed at defining novel mechanisms of HIV-1-induced dysfunction of natural killer (NK) and CD8 T cells. We will investigate the role of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) in well- characterized subjects from the Options study of early HIV-1 infection and the SCOPE study of chronic HIV-1 infection, both based at the University of California, San Francisco. In mice, Tim-3 regulates Th1 responses by binding to its cognate ligand, Galectin-9, to promote T-cell aggregation and the death of interferon-gamma- producing Th1 cells. In our preliminary studies, we found Tim-3 receptors on human CD8 T cells and showed that they are markedly upregulated during progressive HIV-1 infection and may also play a role in the innate immune response. We propose three specific aims:
Aim 1 : To assess the kinetics of Tim-3 expression on NK cells and HIV-1 specific CD8 T cells in primary HIV-1 infection and determine whether Tim-3 expression predicts the viral set point.
Aim 2 : To determine whether Tim-3 expression on HIV-1-specific CD8 T cells is lower in HIV-1 elite controllers than in untreated subjects with progressive disease and antiretroviral-treated subjects with undetectable viral loads.
Aim 3 : To identify the mechanism of Tim-3 induction on NK cells and CD8 T cells by HIV-1 infection and determine whether modulation of the Tim-3 pathway in vitro can reverse effector cell dysfunction. A better understanding of mechanisms of NK cell and CD8 T cell dysfunction in HIV-1 infection through the Tim-3 pathway could lead to new therapeutic modalities to help reverse this immune deficiency.

Public Health Relevance

The goal of this proposal is to investigate how the immune system in HIV-1 fails to eliminate virus, and in particular how NK cells and CD8 T cells, dysfunction in HIV-1 infected patients. We will characterize a novel pathway that leads to these ineffective innate and adaptive immune functions through the study of diverse groups of HIV-1 infected persons, and determine the mechanisms regulating this pathway with the ultimate aim of developing better treatments for HIV-1 infection

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
7R56AI083112-02
Application #
8264231
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2010-09-17
Project End
2012-08-31
Budget Start
2011-06-21
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$240,216
Indirect Cost

  Institution

Name
University of Hawaii
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822

  Publications

Clayton, Kiera L; Haaland, Matthew S; Douglas-Vail, Matthew B et al. (2014) T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol 192:782-91
Crawford, Timothy Q; Hecht, Fredrick M; Pilcher, Christopher D et al. (2013) Activation associated ERK1/2 signaling impairments in CD8+ T cells co-localize with blunted polyclonal and HIV-1 specific effector functions in early untreated HIV-1 infection. PLoS One 8:e77412
Tandon, Ravi; Giret, Maria T M; Sengupta, Devi et al. (2012) Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children. PLoS One 7:e45733
Ndhlovu, Lishomwa C; Lopez-Vergès, Sandra; Barbour, Jason D et al. (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119:3734-43
Crawford, Timothy Q; Ndhlovu, Lishomwa C; Tan, Alice et al. (2011) HIV-1 infection abrogates CD8+ T cell mitogen-activated protein kinase signaling responses. J Virol 85:12343-50
Ndhlovu, Lishomwa C; Leal, Fabio E; Hasenkrug, Aaron M et al. (2011) HTLV-1 tax specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: implications for progression to neurological complications. PLoS Negl Trop Dis 5:e1030