People infected with many serious illnesses, including HIV, may not show symptoms of disease for long periods of time. These inactive, or "latent," infections can develop into active disease without warning and also can be passed on to others. New approaches that focus on controlling or stimulating the immune system to cure latent infections or prevent them from causing disease have the potential to significantly reduce illness, death, and disease transmission.

Dr. Baltimore’s team is exploring a new way of stimulating the immune system to fight infectious diseases, focusing on HIV. The premise of this project is that for some infections, including HIV, the immune system’s natural responses are inherently inadequate, and the traditional approach of using vaccines to stimulate and boost these responses is likely to be ineffective. As an alternative, Dr. Baltimore and his colleagues propose to "engineer immunity," that is, use genetic engineering methods to produce immune cells that will make specific antibodies to fight off infection.

Investigators plan to produce the antibodies in vivo by infecting hematopoietic stem cells (HSCs) with viral vectors bearing specific antibody genes. While they are focusing their initial efforts on HIV, the team expects the method will be applicable to other infectious diseases.
 
Investigators are:

• Adapting their methods of generating T cells to generate functional B cells that, when stimulated with antigen, are capable of secreting antibodies or antibody-like proteins.
• Using their in vitro human B lymphopoiesis culture system to screen for lentivectors that mediate high production of four designer antibodies.
• Achieving high levels of antibody expression in HIS mice and stablishing protocols that will result in consistent and detectable HIV infections that can be analyzed in response to different antibody treatments.
• Achieving gene transfer and expression of three broadly neutralizing anti-HIV antibodies in human lymphocytes and HSC using the lentiviral vector.
• Pursuing several approaches toward making protein reagents that will be more potent than existing neutralizing antibodies, including making bispecific antibodies that contain two different binding sites. 
• Testing the ability of their engineered lentivectors to transduce primary human CD34+ cells in vitro and in a mouse model, with plans to use the CD34-targeting lentivectors to deliver anti-HIV NAb genes into HSCs to treat HIV infection.