Despite years of intensive research, the immunological basis of control of AIDS-virus replication remains poorly understood. Without such knowledge, rational design of an AIDS vaccine is very difficult. In this application we will attempt to understand the constituents of a successful response against the AIDS virus. This information should help us design better vaccines. While most HIV-infected patients will die without treatment, a small number of individuals control viral replication to undetectable levels (elite controllers;ECs). The majority of these ECs express the HLA class I molecules HLA-B*57 or -B*27, implicating CD8+ lymphocytes in the effective control of HIV replication. However, how these patients control HIV replication remains a mystery. Understanding why the immune systems of these patients are successful against such a pathogenic virus might give us key insights into how to make an effective vaccine. Unfortunately, it has been difficult to assess acute phase immune responses against HIV and it is impossible to carry out invasive experiments in humans. We have recently developed an animal model of elite control in Mamu-B*08+ Indian rhesus macaques. Remarkably, 50% of Mamu-B*08+ Indian rhesus macaques control replication of SIV and Mamu- B*08 and HLA-B*27 bind similar peptides. Thus, these Mamu-B*08+ macaques are ideal for modeling human ECs. We can challenge macaques with mutant viruses, analyze the acute phase response to the virus, and determine the virus-specific immune response in tissues. In this proposal we will attempt to determine the major factors that contribute to elite control. Understanding why ECs suppress viral replication should facilitate the development of an effective HIV vaccine. In our first Specific Aim, we will test the hypothesis that Mamu-B*08-epitope-specific T cell responses play a central role in control of SIV replication in macaque ECs. In our second Specific Aim, we will explore the hypothesis that the rate of viral escape determines whether a macaque becomes an EC or progresses normally. In our third Specific Aim, in a collaboration with Danny Douek and David Price, we will determine whether the pattern of immunodominance and the T cell receptor (TCR) used by Mamu-B*08-epitope- specific T cells plays a role in determining EC status. In our fourth Specific Aim, in a collaboration with Ashley Haase, we will explore the hypothesis that Mamu-B*08-specific T cell responses are particularly effective in key sites of viral replication in early infection. We are incredibly excited to carry out the proposed experiments in our novel model of AIDS virus control. The last grant period has enabled us to assemble the tools and collaborative experience to test innovative hypotheses regarding elite control. Furthermore, our grant enabled us to make the discovery that Mamu- B*08+ macaques control SIV replication. Our findings in the macaque model should be directly relevant to understanding why particular humans control HIV replication;discoveries that may aid HIV vaccine development. PUBLIC HEALTH RELEVANCE: We will explore several novel, innovative hypotheses as to why certain individuals control viral replication. Results from these studies should help us understand why some humans suppress HIV replication. Furthermore, this understanding of a successful immune response to the AIDS virus should aid in vaccine design.