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.
