Engineering Immunity against HIV - a Stem Cell Vaccine

Kenneth Yu, California Institute of Technology
Advisor: David Baltimore
Training in Basic Biomedical Sciences
Dissertation Award

An effective vaccine against the human immunodeficiency virus (HIV)-1 has so far been elusive. We propose a novel approach to HIV vaccination, captured in the terms of “Engineering Immunity” or “Instructive Immunity.” 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 a neutralizing antibody response with sufficient quality and breadth to cover the diversity of HIV variants. An immunogen that elicits a broadly neutralizing antibody (bNAb) response has been difficult to develop. However, some bNAbs against HIV have been immortalized as monoclonal antibodies. We can therefore overcome the difficulty posed by the lack of a good immunogen by using gene therapy to directly instruct the the immune system to produce anti-HIV bNAbs.

We propose to program human B cells to produce these anti-HIV bNAbs, by modifying the long-lived hematopoietic stem cells (HSCs) with lentiviral vectors carrying engineered bNAb genes. When transplanted into susceptible individuals, these modified HSCs will provide a life-long supply of HIV-specific B cells and anti-HIV bNAbs that protect the recepients from HIV infection; in effect, an anti-HIV “stem cell vaccine.”

To program the development of HIV-specific B cells from HSCs, it is necessary to express both the membrane-bound antibody (the B-cell receptor, or BCR) and secreted antibody. To achieve this goal, we have devised a wholly new way of antibody expression, which we term a “Synthetic Switch” antibody gene. Taking advantage of a ribosomal partial termination process, we are able to co-expresses functional anti-HIV BCR and secretory bNAb genes in B lineage cells. Armed with this novel expression system, we will test the HYPOTHESIS that bNAbs produced from HIV-specific B cells derived from engineered HSCs can protect against HIV infection. We will examine this hypothesis by accomplishing the following two SPECIFIC AIMS:

Specific Aim 1: To determine if HSCs lentivirally transduced with a Synthetic-Swtich bNAb gene are capable of developing into HIV-specific B cells that can produce anti-HIV antibodies.

Specific Aim 2: To determine if transplantation of HSCs lentivirally transduced with Synthetic-Switch bNAb genes are able to confer protection against HIV infection in vivo.

The completion of this work will provide insights into anti-HIV immunity. Specifically, we will understand whether humoral immunity in the form of bNAbs against HIV is sufficient to confer protection against HIV infection. Furthermore, the work establishes the Instructive Immunity paradigm by providing a practical method to progarm human B cells to produce antibodies of pre-defined specificities. This is a general approach that can be used in the treatment or prevention of other infectious diseases. Significantly, the work will critically test the concept of an anti-HIV stem cell vaccine in an in vivo small animal model. If found to be efficacious at preventing HIV infection, it will provide a prototype vaccine for further clinical testing.