Human CD8+ T cells play an important role in controlling HIV and SIV disease progression, but the precise mechanisms involved in control remain unclear. CD8+ T cells are capable of multiple effector functions, including cytolysis and production of various cytokines and chemokines. It is now possible, through polychromatic flow cytometry, to measure at least five CD8+ T cell functions simultaneously. The functional profile of HIV-specific CD8+ T cells using this technique is highly complex, and variable between different HIV antigens and disease progression states. We hypothesize that the functional nature of the HIV-specific CD8+ T cell response can vary between individual HIV epitopes, and therefore place differential selective pressure upon HIV epitopes to influence escape mutation. The ability of a particular CD8+ T cell functional profile to induce escape would indicate that it has an adverse effect on viral replication.
Specific Aim #1 will determine if, within an HIV-infected individual, the functional nature of the CD8+ T cell response to distinct HIV epitopes is variable. We will perform epitope-mapping studies employing polychromatic flow cytometry to identify CD8+ T cell functional profiles to multiple HIV epitopes, and whether differential thresholds exist for multiple CD8+ T cell functions. Finally, we will examine CMV, EBV, and influenza virus-specific CD8+ T cell functionality to identify differential functional ability within and between these viruses and HIV.
In Specific Aim 2, we will determine if particular CD8+ T cell functional profiles place differential selective pressure upon HIV epitopes. We will examine epitope escape mutations for recognition by subjects with appropriate epitope-specific CD8+ T cells for altered functionality in response to escape epitopes. The long term goal of this project is to determine if escape mutation occurs as a result of particular CD8+ T cell functional patterns. Defining the role of different CD8+ T cell functional patterns at the epitope level will lead to insights into disease pathogenesis and immune correlates of protection for HIV vaccine modalities. (Lay language description): The human immune system is able to control HIV disease progression, but the underlying mechanisms are unclear. This proposal seeks to determine what aspects of the HIV-specific immune response are important in controlling HIV. Our findings will further our understanding of HIV disease, and assist in the development of an HIV vaccine.
