HIV infection is a major public health problem in California and abroad. Current treatments do not cure HIV infection and require lifelong medications that are expensive and often associated with serious side effects. To address the clear need for improved treatments for HIV infection, we propose to develop a cell therapy based approach. Specifically, we aim to modify a gene that encodes a cell surface protein (CCR5) that is crucial for HIV entry into the cell, yet non-essential for normal cell function.
HIV causes AIDS by infecting various types of immune cells that each express CCR5 and arise from a common parental cell type called a hematopoietic stem cell (HSC). Studies have shown that HIV replication is substantially reduced if the virus is prevented from binding to CCR5. In fact, rare individuals who have naturally mutated CCR5 genes are highly resistant to HIV infection. Thus, we propose that HIV-infected individuals would benefit from having cells with CCR5 mutations, similar to those found in naturally resistant individuals. This CCR5 mutation need only be present in HSC, as these cells will then develop into a variety of immune cell types having the CCR5 mutation.
A challenge for this therapeutic approach is mutating the CCR5 gene in HSC, because these cells are rare (<1 per microliter of blood) and they are difficult to permanently genetically modify. However, HSC can be converted into induced pluripotent stem (iPS) cells in the laboratory. The resulting iPS cells can then be grown to appreciable numbers to allow for CCR5 mutation procedures. The CCR5-mutant iPS cells can then be converted back into HSC and re-administered to the HIV-infected patient.
Our cell therapy approach is supported by a recent clinical model where an HIV-infected patient received HSC from an uninfected individual who had CCR5-mutant cells. Now three years following this procedure, the HIV-infected patient shows no evidence of HIV-replication, despite the absence of antiretroviral drugs. Importantly, individuals who naturally have these CCR5-mutant HIV-resistant cells are rare (<1% of the population). Moreover, such transplantations of cells can only take place between genetically compatible individuals. Therefore, while this clinical model is encouraging for future directions such as proposed here, it is not directly applicable to the majority of HIV-infected individuals. Our cell therapy approach addresses the limitations of the clinical model and could be directly beneficial to a much larger number of HIV-infected individuals.
Statement of Benefit to California:
HIV infection is a major public health problem in California and abroad. Current treatments do not cure HIV infection and require lifelong medications that are expensive and often associated with serious side effects. To address the clear need for improved treatments for HIV infection, we propose to develop a cell therapy based approach. Successfully applied, this therapy should 1) be of clinical benefit to HIV-infected individuals in California, 2) lower the risk of HIV infection for Californians, and 3) reduce to health care expenditures incurred by the state of California and its citizens. Moreover, this research will help California maintain its place as a leader in HIV research and medical research in general.