During more than 20 years of research, cell and gene therapy products were developed and tested as potential treatments or cures for HIV disease. Here, we examine recent progress and highlight the potential for cell and gene therapy to deliver the sought-after cure.

The history of cell and gene therapy for HIV traces back to at least 1994 when Roberts et al[1] used a retroviral vector to reprogram T cells to express a major histocompatibility complex (MHC)-unrestricted recognition molecule. The recognition molecule was a truncated form of the CD4 glycoprotein receptor for HIV and the engineered cells were expected to detect and destroy infected cells that expressed cell surface envelope glycoprotein. This was an early form of what we know today as Chimeric Antigen Receptor (CAR) mediated and MHC-unrestricted recognition of cellular antigens. In the ensuing years, T cells have been engineered to recognize infected cells using multiple receptors, resist HIV attachment, and inhibit virus replication. Genetic modifications have been made to circulating lymphocytes or hematopoietic stem cell precursor cells (HSCPC) and cells were infused during clinical trials to test whether they controlled the rebound of plasma viremia following interruption of therapy. Save for the example of cells edited ex vivo to disrupt the CCR5 gene and infused into a trial participant heterozygous for the CCR5delta32 loss of function allele [2], stable suppression of HIV in the absence of antiretroviral drug therapy has not been achieved.