The majority of HIV-infected individuals will eventually experience an increase in viral load and a decline in CD4+T cells, leading to AIDS, unless HAART is administered. However, ~1/200-1/500 individuals are able to naturally control the virus in the absence of therapy, retaining normal CD4+ T cell levels and resisting progression to AIDS indefinitely. These elite controllers (ECs) have been the subject of intensive study. We have collected a cohort of 21 ECs from the local Yale/VA community and through collaborative efforts with investigators at Vanderbilt University. In a preliminary study, we found that CD4+ T cells from several ECs were resistant to M-tropic single cycle HIV infection ex vivo. We also performed exome sequencing on these individuals (i.e. sequencing of all the coding sequences within the genome) and identified approximately 300 rare gene variants, including single nucleotide polymorphisms and insertions/ deletions. However, the task of identifying which of these variants contribute to elite control has proved challenging. In this study we will comprehensively characterize the resistance to HIV infection that we observed in the CD4+ T cells of several ECs. We will harness the power of a familial study to examine if there is a heritable component to this phenotype. We will then perform exome sequencing to identify rare gene variants that are associated with this phenotype. We will also perform transcriptome analysis, to identify gene expression patterns that are associated with this phenotype.