A genetic basis for resistance to infection by HIV-1

The Human Immunodeficiency Virus 1 (HIV-1) pandemic continues unabated despite increasing public health efforts and intense research. Considerable effort has gone into the development of HIV vaccines, and natural model of resistance to HIV-1 would be invaluable in this endeavor. Within a sex worker cohort in Nairobi, Kenya we have identified a group of women who are resistant to infection by HIV-1.; Resistance correlates with cellular and mucosal immune responses to HIV-1 suggesting that these woman have developed acquired immunity to HIV-1 thus providing a natural model of immunity. The question remains however as to why do these women appear to be able to mount an effective immune response to HIV-1 while the vast majority of individuals are unable to? It is our hypothesis that resistance to HIV-1 is mediated by genetic factors that are involved in the regulation of protective immune responses to HIV-1.; Using the tools of epidemiology, immunology, and genetics we provide data to show that there is a genetic basis for resistance to infection by HIV-1. We show that individuals related to a HIV resistant woman are less likely to become infected by the HIV-1 virus compared to individuals related to an HIV susceptible woman. This strongly suggests that there is a genetic component responsible for resistance to infection by HIV-1. To further investigate this finding we investigated polymorphisms in a number of genes involved in immune responses to HIV-1. These included microsatellite markers in a region important in regulating cellular and humoral immune responses. We identified an allele in the immunoregulatory molecule Interferon Regulatory Factor 1 (IRF-1) that was found at an increased frequency in HIV resistant women. This allele (IRF-1 179) was associated with the resistance phenotype and was shown to protect against HIV infection. This is the first report of a polymorphism in a transcription factor that may account for differential susceptibility to HIV-1. We believe that individuals with the IRF-1 179 allele are better able to respond to HIV with what has been proposed to be protective cellular immune responses. This finding confirms our hypothesis that there are genetic factors responsible for resistance to infection by HIV-1.