In absence of antiretroviral therapy (ART) almost all HIV-infected patients will progress to AIDS. However, a rare group, the elite controllers (EC), have a natural ability to control HIV replication in the absence of ART, but the mechanisms by which they achieve this phenotype have not been explored. I hypothesize that differential mechanisms of disease control and heterogeneous host genetic traits are associated with immune control of HIV-1 replication in EC. In my research program, using high throughput genomics, transcriptomics and proteomics (aim 1 and 2) and integrating the multi-omics data (aim 3), I seek to understand the host-specific networks and mechanisms that control HIV-1 replication in EC. We will use longitudinal biobanked plasma, freshly drawn blood and gut biopsies from very well-characterized patient-populations. Finally, in aim 4 we will map the molecular pathways of HIV-1 pathogenesis and its control. targeting the three to four pathways that are identified in aim 1-3. My study will thereby generate a huge knowledge in the field of HIV-1 control. This understanding of the unique gene expression and immunological characteristics of EC will predict a frame of reference for what may be required in clinical intervention strategies to induce immune control of HIV-1 and the future development of functional HIV-cure.