GENETIC EPIDEMIOLOGY OF AIDS AND THE ROLE OF CHEMOKINE GENES

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A series of in vivo and in vitro studies has identified a number of cellular genes that play pivotal roles in the infectivity of HIV and in the disease progression of AIDS in infected individuals. One such group of genes includes the chemokines. Chemokines are small heparin-binding proteins that chemoattract monocytes, neutrophils, and T-cells, and serve as mediators of inflammation. It has been shown in the past year and one-half that the receptors for these chemokine ligands are used as co-receptors for HIV, providing the virus a docking port for entry into cells. We are currently carrying out a mutation analysis of all 32 human chemokine genes in a series of clinically well-defined patient cohorts. Five cohorts were assembled by several collaborating units and collectively consist of about 3000 individuals who can be assigned to one of three major clinical categories: exposed, uninfected; rapid progressors; and long-term survivors. We are in the process of designing polymerase chain reaction primers for different regions of all human chemokine genes. The genes are being screened using the single strand conformational polymorphism (SSCP) procedure on a panel of 144 individuals that are divisible into six subcategories based upon race and clinical disposition. Any SSCP variants appearing at appreciably different frequencies between cohorts will be sequenced and converted into a restriction fragment length polymorphism assay for screening larger numbers of individuals. At the present time, potentially informative polymorphisms have been identified in several genes. One of these genes, SDF-1, has been extensively characterized and appears to delay disease progression in Caucasians. (See Project Z01 BC 10264-01 LGD).