The rate of progression to AIDS among HIV-infected subjects is controlled by a number of poorly understood factors. Certain HLA alleles are associated with spontaneous control of viral replication, and empirical and computational evidence suggest that T cell clonotypes restricted by protective alleles may have intrinsically enhanced capabilities for controlling viral replication and escape compared to other T cells. We propose new approaches to examine the intrinsic antiviral capacity of T cell clones specific for non-HIV antigens using a chimeric viral system incorporating transposed epitopes. A major barrier to understanding how the immune system may control viral replication is the chicken and the egg problem. Thus subjects with low viral loads may have indications of a more robust immune system; however, it is difficult to say whether the robust immune response is a cause of low viral loads or an effect. In order to get around this problem, we have developed a new experimental system that will allow us to measure the anti-HIV potential of immune cells from healthy uninfected people. To accomplish this, we transpose a short genetic sequence (encoding and epitope) from a ubiquitous pathogen such as human respiratory syncytial virus (HRSV) into the HIV genome. In out preliminary data, we show that such a chimeric HIV construct is vulnerable to attack by HRSV-specific immune cells from a healthy donor. This novel system gives us an opportunity to ask many questions about what makes certain immune responses special . Because it is known that the immune-related gene allele HLA B57 is associated with protection from HIV disease, we hypothesize that immune cells (cytolytic T lymphocytes) that interact with HLA B57 are intrinsically better at shutting down HIV compared to other CTL. We will use our transposed epitope system to test out this possibility.
In the absence of antiretroviral medication the vast majority of people infected with HIV fail to control HIV replication, and thus progress to AIDS. The rate of progression varies widely among individuals, such that some rare subjects??Elite Controllers?-- can suppress viral replication to undetectable levels without medication. Variations in certain genes related to the immune system are known to be associated with the elite control phenomenon. We will investigate the biochemical basis for control.
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