139th National Cancer Advisory Board
treatments, particularly in the drug resistance area. Because patients are living longer, many of these patients are coming down with a higher frequency of malignancies; for this reason, a significant component within the CCR deals with AIDS-associated malignancies.
The CCR is also a comprehensive translational research program. It addresses nine areas: (1) cancer biology and etiology also; (2) HIV/AIDS research; (3) molecular targets and molecular oncology; (4) immunology, immunotheraphy, and immunoprophylaxis; (5) genetics and genomics; (6) imaging and biomarkers; (7) advanced biomedical technologies; (8) clinical infrastructure and support; and (9) CCR infrastructure. Dr. Wiltrout next presented a graphic to illustrate the infrastructure used to support translational multidisciplinary research across these nine areas. The infrastructure included: training, faculty, Center of Excellence, drug development, imaging, programs and initiatives, cores, HIV/AIDS, and epidemiology.
The CCR’s mission includes the establishment of partnerships, such as between CCR laboratories and branches, across the NCI and the NIH, and between intramural and extramural investigators. Collaborations also are fostered with industry, pharmaceutical companies, other federal agencies, and national and international consortia, among others. Dr. Wiltrout shared a list of areas in which CCR funds are leveraged in support of intramural-extramural partnerships. Several of these include the Leukemia and Lymphoma Molecular Profiling Project, the HPV vaccine, and the Phase O initiative.
Dr. Wiltrout next introduced several of NCI’s mid-career scientists to present to the NCAB some of the exciting investigations that are occurring in their laboratories. Dr. Mary Carrington will discuss hosting genetic variation and dramatic consequences for HIV disease. Dr. Javed Khan will talk about his studies with artificial neural networks, as well as a new, multi-agency initiative to develop approaches for gene discovery and analysis. Dr. David Wink will describe NCI’s Redox Faculty. Finally, Dr. Steven K. Libutti will talk about the trans-NIH angiogenesis research program.
Influence of Immunogenetic Variation on HIV Disease—Dr. Mary Carrington
Dr. Carrington presented a scientific update on research concerning the influence of immunogenetic variation on HIV disease. Host genetic variation can influence the likelihood of HIV infection as well as disease progression after HIV seroconversion. The HLA class I genes, located in the major histocompatibility complex on chromosome 6, and the killer immunoglobulin-like receptor (KIR) gene cluster, located in the leukocyte receptor complex on chromosome 19, appear to play roles in this process. The products encoded by the HLA Class I genes and KIR genes serve as receptors and ligands for one another and are highly polymorphic. HLA Class I genes show extreme allelic polymorphism— there are many forms of a single gene. The KIR genes also show substantial allelic polymorphism and are polygenic in nature as well. Across haplotypes in humans, the number and type of KIR genes that present on chromosome 19 varies.
Natural killer (NK) cells represent the first line of defense against viral infection as well as tumor development. NK cells express a number of different receptors that regulate their activity, including KIRs. When inhibitory KIRs interact with their ligands, which are a specific HLA Class I allotype, a signal is sent to the NK cell not to kill the target because it has healthy, normal Class I expression. Some virally infected cells and tumor cells downregulate HLA Class I ligands; lack of inhibitory KIR ligands allows an activating receptor to send a signal to the NK cells to kill these cells.
Two genes that have been of particular interest regarding HIV infection are HLA-B and KIR3DL1, which encode molecules that serve as ligand and receptor. HLA-B is the most polymorphic gene in the human genome identified to date and KIR3DL1 also is highly polymorphic. In both cases, the polymorphism has been shown to have functional significance, resulting in differential binding between