Global Analysis of HIV Cellular Restriction

Sumit Chanda, Burnham Institute for Medical Research, La Jolla
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)

Innate immunity is the first line of defense against foreign pathogen invasion. Viruses must successfully disarm these host protective mechanisms to establish productive infections. Disabling these viral countermeasures is an attractive strategy for the development of novel antiviral therapies that target host cellular factors. However, the molecular interactions that underlie these processes are not fully appreciated for many viruses, including Human Immunodeficiency Virus (HIV). We propose to pursue a novel systems-based strategy to enable the global identification of cellular molecules that restrict infection by HIV. This approach will be the first to validate a comprehensive set of HIV 'restriction' factors that impinge upon viral replication, and will provide the foundation from which we can study the strategies by which HIV evades innate immune defense mechanisms. We aim to validate and characterize candidate genes that restrict HIV infection that we have recently identified through genome-wide RNAi and cDNA functional genomic analysis of HIV replication (Konig et al., Cell, (2008), unpublished data). Specifically, we propose to: (i) retest and confirm the activities of approximately 200 genes, which were identified through the genome-wide analysis to restrict HIV infectivity and (ii) categorize their roles in the innate immune response to HIV infection. A global survey of these critical host-pathogen interactions will open a series of new opportunities for future studies to understand the mechanistic basis of HIV cellular restriction, and provide new therapeutic targets for the development of ‘first-in-class’ immune-mediated antiviral treatments.