There remains a subset of HIV-infected patients who maintain undetectable plasma HIV RNA levels (elite controllers) that make up approximately 1% of the HIV-infected population. The mechanism for this unique status is the subject of intensive research, but remains unknown. The objective of this proposal is to determine how a set of six cytokines found to be elevated in the serum of HIV elite controllers influences viral replication and cellular activation. The central hypothesis of this proposal is that the eight cytokines that were found to be elevated in the serum of elite controllers from the WIHS cohort enables control of viral replication and cellular activation thus limiting disease progression. The specific aims are: (1) To determine the effect of these cytokines individually or in combination on viral replication and how they influence the course of virus infection; and (2) To characterize the phenotypic and functional effect of these cytokines individually and in combination on immune mediators in PBMC. To address these aims PBMC will be infected in the presence or absence of cytokines alone or in combination and viral replication will be assessed by production of p24. Additionally, PBMC will be stimulated in the presence or absence of these cytokines and assessed for immune activation. The completion of this project will provide insight as to how elite controllers are able to control viral replication and prevent disease progression. This information is critical as there is currently no effective vaccine to protect from HIV and one strategy for HIV vaccine design would be to mimic the immune response to HIV observed in EC. In the long-term, having a firm understanding of how these cytokines influence viral replication and cellular activation is paramount to effective vaccine design and drug development.