Effector CD8+ T cells in HIV infection are responsible for initial viremia control, however, HIV-specific CTL memory cells are lost during disease progression by an unknown mechanism. Our data show that HIV+ patients contain HIV-specific CD8+CD28 m cells which die by costimulation via monocytes. hi addition, we found that HFV causes over-expression of the CD28 ligands (CD80 and CD86) in vitro, inducing CD28 loss and apoptosis of CD8+ T cells. These observations suggest a fundamental mechanism whereby CD8+ T cells capable of becoming memory HIV-specific CTL could be selectively lost during disease progression. To study this hypothesis we propose three aims.
Aim 1 examines mechanisms for CD28 down-regulation and apoptosis. Using mixtures of CHO cell lineswith defined levels of costimulatory ligands, CD80 or CD86, incubated with purified T cells, we will assess mechanisms responsible for CD28 down-regulation and apoptosis. To examine the importance of HIV infection, we will mix autologous HIV-infected macrophages with T cells, examine CD80 and CD86 expression on the macrophages, as well as the effects of cell contact, soluble factors or cytokines released by the macrophages on CD28 down- regulation and apoptosis of the CDS T cells. Because little is known about molecular regulation of CD28 expression, Aim 2 will examine the down-regulation of the CD28 promoter by testing differential binding of NF- kBa and/or STAT-6 proteins, which will provide a molecular basis for prevention of CD28 loss. Ann 3 willdevelop potential therapeutic methods to increase antigen-specific memory CD8+ T cells in HIV. Using alloantigen as a model, we will modulate costimulation, activation conditions, timing, strength of signals, and cytokines. The most promising methods to increase memory CD8+ T cells will be used with CD8+ T cells from HIV-infected patients. Because CD8+ T cells are important for HIV control, these studies are important for development of immune intervention strategies and for vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37AI036682-15
Application #
7788785
Study Section
Special Emphasis Panel (NSS)
Program Officer
Embry, Alan C
Project Start
1995-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
15
Fiscal Year
2010
Total Cost
$347,627
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Fadul, Nada; Couturier, Jacob; Yu, Xiaoying et al. (2017) Treatment-Naïve HIV-Infected Patients Have Fewer Gut-Homing ?7 Memory CD4 T Cells than Healthy Controls. South Med J 110:709-713
Couturier, Jacob; Hutchison, Alexander T; Medina, Miguel A et al. (2014) HIV replication in conjunction with granzyme B production by CCR5+ memory CD4 T cells: Implications for bystander cell and tissue pathologies. Virology 462-463:175-88
Lin, Lin; Couturier, Jacob; Yu, Xiaoying et al. (2014) Granzyme B secretion by human memory CD4 T cells is less strictly regulated compared to memory CD8 T cells. BMC Immunol 15:36
Medina, Miguel A; Couturier, Jacob; Feske, Marsha L et al. (2012) Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells. J Leukoc Biol 91:759-71
Hutchison, A T; Schmitz, J E; Miller, C J et al. (2011) Increased inherent intestinal granzyme B expression may be associated with SIV pathogenesis in Asian non-human primates. J Med Primatol 40:414-26
Singh, Manisha; Basu, Sreemanti; Camell, Christina et al. (2008) Selective expansion of memory CD4(+) T cells by mitogenic human CD28 generates inflammatory cytokines and regulatory T cells. Eur J Immunol 38:1522-32
Lewis, Dorothy E; Merched-Sauvage, Maria; Goronzy, Jorg J et al. (2004) Tumor necrosis factor-alpha and CD80 modulate CD28 expression through a similar mechanism of T-cell receptor-independent inhibition of transcription. J Biol Chem 279:29130-8
Lewis, D E; Ng Tang, D S; Wang, X et al. (1999) Costimulatory pathways mediate monocyte-dependent lymphocyte apoptosis in HIV. Clin Immunol 90:302-12
Lewis, D E; Yang, L; Luo, W et al. (1999) HIV-specific cytotoxic T lymphocyte precursors exist in a CD28-CD8+ T cell subset and increase with loss of CD4 T cells. AIDS 13:1029-33
Lloyd, T E; Yang, L; Tang, D N et al. (1997) Regulation of CD28 costimulation in human CD8+ T cells. J Immunol 158:1551-8