139th National Cancer Advisory Board
KIR3DL1 and HLA-B subtypes. For example, KIR3DL1001 interacts with high affinity with a certain set of HLA-B allotypes, including B57, the most protective HLA allotype against HIV disease. The same KIR3DL1 subtype interacts with low affinity with a different group of HLA-B allotypes, including B27, another allotype that is protective against HIV. There also is a set of HLA-B allotypes that do not serve as ligand for KIR3DL1, for example B45; this group of alleles is known as Bw6. Individuals homozygous for Bw6 have no ligand for KIR3DL1 and thus serve as a control group for studying protective effects between specific combinations of KIR3DL1 and HLA-B subtypes.
Five AIDS cohorts, in which dates of seroconversion are known for each participant, have been used to study the effects of compound genotypes of KIR3DL1 and HLA-B on progression from seroconversion to an AIDS-defining illness. Individuals with specific combinations of KIR3DL1 and HLA-B progress slowly to AIDS relative to those who do not have the ligand for KIR3DL1 (individuals homozygous for Bw6). There are multiple distinct, independent effects of KIR3DL1 and HLA-B subtypes on HIV disease. The most protective HLA-B allele is B57; a combination of specific KIR3DL1 alleles plus B57 confers greater protection against HIV disease progression relative to any other genetic variant identified to date in these cohorts. The protection conferred by this combination of KIR3DL1 and HLA-B alleles also appears to apply to cervical neoplasia, which may indicate that combinations of these genes could offer varying degrees of protection against multiple diseases. These complex, abundant, epistatic or synergistic effects between KIR3DL1 and HLA-B are unprecedented with regard to any pair of genetic loci in human disease.
Questions and Answers
Dr. Daniel Von Hoff, Director, Translational Drug Development Division, Translational Genomics Research Institute, University of Arizona, asked about the sample size for the populations used in this study. Dr. Carrington answered that there were 1,400 seroconverters from the five cohorts, with perhaps 20 individuals per low frequency genotype or several hundred individuals for higher frequency genotypes. There were 67 individuals who had the highly protective combination of KIR3DL1 and HLA- B alleles.
Dr. Chabner asked if Dr. Carrington had worked with Dr. Bruce Walker, who has reported a cohort of men who seroconverted but never developed AIDS. Dr. Carrington responded that her laboratory is currently working with Dr. Walker to genotype these “elite controllers” with regard to KIR and HLA typing. She mentioned working with Dr. Mark Connors at the National Institute of Allergy and Infectious Diseases (NIAID), who also has identified a group of individuals who have controlled their HIV infections well. The protective KIR3DL1 and HLA-B genotypes have been found at high frequency among these patients, and it is likely that the same will be true for Dr. Walker’s group. Dr. Freedman asked whether there was evidence that vaccines might work better in people with the protective genotypes. Dr. Carrington replied that currently there is no evidence for this, because there are no strongly protective vaccines. She added that developing therapies that increase NK cell activity probably would be useful; experiments performed in vitro and in macaques suggest that increased NK cell activity is beneficial for viral control.
Microarrays and Artificial Intelligence for Diagnosis, Prognosis, and Selection of Therapeutic Targets in Cancer—Dr. Javed Khan
Dr. Khan explained investigative work underway to use microarrays and artificial intelligence in the diagnosis, prognosis, and selection of therapeutic targets for cancer. Cancer artificial neural networks (ANNs) can be used to diagnosis cancers using gene expression profiles and to predict prognosis. ANNs are powerful pattern recognition algorithms modeled on the human brain. These algorithms are highly