The research work contained in this application for RFA AI-94-029 """"""""Pediatric AIDS: Factors in Transmission and Pathogenesis"""""""" will focus on immune factors that allow certain HIV+ children to become long-term survivors (LTS). Specifically, the proposal will concern the role of the cytotoxic T lymphocyte (CTL) in preserving the lives of HIV vertically infected children up to the early teens. The preliminary findings contained in this project are an outgrowth of a previous NIH grant award, ROl HD26603 """"""""Improved Methods for Detecting HIV in High-Risk Neonates"""""""". The long-term objective of this research proposal is to establish the immunological mechanisms that permit up to third of HIV vertically infected children to live well beyond 5 years of life, in contrast to those rapid progressors who expire from opportunistic infections and severe immunosuppression within the first few years of life.
Specific Aim 1 is to conduct a longitudinal study of children who, in the course of the study, will represent rapid progressors, intermediate progressors, and LTS. CD8+ cell phenotype and function will be examined including loss of the CD28 antigen, development of anergy to T cell stimulation, increase in apoptosis, and loss of HIV-specific C recursors. These parameters will be correlated with viral load and clinical progression.
Specific Aim 2 is to determine whether cytokine production patterns in stimulated T cells are altered in children with progressing infection compared to those in children who are LTS. It is predicted that those children who produce primarily helper cell type l (T-l) cytokine profiles when stimulated in vitro will more likely be LTS.
Specific Aim 3 is to examine mechanisms associated with the loss of CD8 CTL precursors in HIV+ children. We will examine the effect of culture conditions including cytokine environment on the development of CD8+ CTL in vitro. It will be determined whether CD28+ and CD28- CD8+ T cells have equivalent CTL precursor frequencies for both HIV and control antigens. Finally, assessment will be made as to whether alterations in antigen presenting cell, i.e. monocyte, function could account for loss of CD28. The research design and methods include recruitment and 5-year study of 36 intermediate progressors and LTS and 3 rapid progressors in our HIV Pediatric Research Center, determination of the rate of loss of CDS+ CD28+ CTL in LTS, assessment of the influence of T-l and T-2 cytokines on declining CTL function, and investigation of the mechanism(s) of CTL loss from HIV+ children, including abnormalities of antigen-presenting cells. It is the hope of the investigators of this project that the discoveries of the importance and mechanism(s) of preservation of CTL function in pediatric LTS, which permit a much longer existence with an improved quality of life, may be exploited therapeutically in the future to enhance restoration of immunity and elimination of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI039131-01
Application #
2076239
Study Section
Special Emphasis Panel (SRC (64))
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Lee, Bang-Ning; Follen, Michele; Rodriquez, Graciela et al. (2006) Deficiencies in myeloid antigen-presenting cells in women with cervical squamous intraepithelial lesions. Cancer 107:999-1007
Lee, Bang-Ning; Follen, Michele; Shen, De-Yu et al. (2004) Depressed type 1 cytokine synthesis by superantigen-activated CD4+ T cells of women with human papillomavirus-related high-grade squamous intraepithelial lesions. Clin Diagn Lab Immunol 11:239-44
Reuben, James M; Lee, Bang-Ning; Paul, Mary et al. (2002) Magnitude of IFN-gamma production in HIV-1-infected children is associated with virus suppression. J Allergy Clin Immunol 110:255-61
Nance, Christina L; Shearer, William T (2002) SDF-1alpha regulates HIV-1-gp120-induced changes in CD79b surface expression and Ig production in activated human B cells. Clin Immunol 105:208-14
Lee, B N; Hammill, H; Popek, E J et al. (2001) Production of interferons and beta-chemokines by placental trophoblasts of HIV-1-infected women. Infect Dis Obstet Gynecol 9:95-104
Patke, C L; Shearer, W T (2000) gp120- and TNF-alpha-induced modulation of human B cell function: proliferation, cyclic AMP generation, Ig production, and B-cell receptor expression. J Allergy Clin Immunol 105:975-82
Lin, H J; Siwak, E B; Lauder, I J et al. (1998) Selection of appropriate HIV-1 genomic regions for single-strand conformation polymorphism analysis of the diversity, modification, and transmission of HIV-1 quasispecies. J Acquir Immune Defic Syndr Hum Retrovirol 18:409-16
Noroski, L M; Shearer, W T (1998) Screening for primary immunodeficiencies in the clinical immunology laboratory. Clin Immunol Immunopathol 86:237-45
Lee, B N; Lu, J G; Shen, D Y et al. (1997) Quantification of IL-2 and IL-2 receptor mRNA in peripheral blood mononuclear cells by the RT-PCR based SHARP Signal system. Cytokines Cell Mol Ther 3:33-40
Lee, B N; Ordonez, N; Popek, E J et al. (1997) Inflammatory cytokine expression is correlated with the level of human immunodeficiency virus (HIV) transcripts in HIV-infected placental trophoblastic cells. J Virol 71:3628-35