HLA restriction and TCR affinity in HIV

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

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 [unreadable]chicken and the egg[unreadable] 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 [unreadable]special[unreadable]. 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.