This CIRM grant was designed to explore the potential to genetically manipulate human embryonic stem cells (hESC), to develop new approaches to combat and protect against AIDS virus (HIV) infection. This is an important goal, because even though current anti-HIV medications are quite beneficial, they are expensive, may have unwanted side effects, and must be taken for the remainder of the patient’s life. Stem cell gene therapy approaches may have the ability to provide long-term protective effects for the patient. HIV infects several different types of blood cells, most notably CD4+ T cells and macrophages. Both of these cell types express CD4, the protein that allows the virus to attach to and infect the target cell. Our initial studies optimized macrophage and T cell development from hESC, which has allowed us to introduce our candidate genetic approaches into hESC, and then test the ability of these genes to function in these blood cells derived from hESC. Several different approaches are being tested, some in hESC and others in hematopoietic stem cells (HSC) to maximize the potential for controlling or eliminating HIV from the body of infected individuals. These are in various stages of development. One area that has shown promise, which initially involved the use of HSC as a prelude to working with hESC, is engineering stem cells such that mature cells that develop from these stem cells can actually attack HIV infected cells. This type of technology could be extended to other chronic infectious diseases or cancers. A second approach involves manipulating cells such that they control virus replication. Development of this latter approach is ongoing. It is our hope that genetically manipulated hESC will allow us to replace cells lost to HIV infection with cells protected against viral infection, and/or to develop strategies that allow the body to defend itself against infection.