Engineering Immunity Against HIV

Citation

Yu, Kenneth Kwok-Chang (2012) Engineering Immunity Against HIV. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/GFQ8-M763. https://resolver.caltech.edu/CaltechTHESIS:04162012-151100376

Abstract

An effective vaccine against the human immunodeficiency virus (HIV)-1 has so far been elusive. Anti-viral vaccines against other viruses work by stimulating the production of neutralizing antibodies that block infection. To be useful, an anti-HIV vaccine preparation needs to elicit potent neutralizing antibody response with sufficient breadth to cover the diversity of HIV variants. Despite sustained research efforts, such an immunogen has been difficult to develop. We could overcome this difficulty by using gene therapy to directly instruct the body to produce anti-HIV broadly neutralizing antibodies (bNAbs). In this thesis, I describe a technology I developed termed the “Molecular Rheostat” for directing the simultaneous expression of anti-HIV surface and secreted immunoglobulins using mutant 2A “self-cleaving” peptides. I describe the application of this system to the programming of hematopoeitic stem cells to generate anti-HIV B cells as a strategy to “vaccinate” against HIV infection. I then pivot to consider alternatives to B-cell programming to produce antibodies against HIV. I investigate the modification of non-lymphoid hematopoietic cells to produce antibodies using retroviral vectors and describe the use of lentiviral vectors to program muscle to produce anti-HIV broadly neutralizing antibodies. In addition to presenting a novel tool for controlling the simultaneous expression of full-length and truncated proteins, the work described here furnishes a foundation for future development into potential gene-therapeutic prophylaxis against HIV.

Thesis Files