The Berlin Patient and CCR5

Tim Brown: the only man to have been cured of HIV  Brown was diagnosed with HIV in 1995  11 years on antiretroviral therapy (ART) before he learned he had developed leukemia  Chemotherapy failed, so doctors proceeded with a bone marrow transplant  The transplant cured his cancer, and the virus dropped to undetectable levels and never bounced back, though he had stopped ART

Three ways the bone transplant could have cured HIV 1.Brown’s immune system was destroyed by chemotherapy and radiation to prepare him for the transplant. This conditioning could have killed all the HIV infected cells in his body. 2.The transplanted cells could have attacked Brown’s own cells, and destroyed any remaining HIV reservoirs. 3.The individual from which Brown received the transplant had a rare mutation that altered one of the receptors (CCR5) HIV uses to get in white blood cells.

Further research was conducted… An experiment was done involving monkeys, to test if irradiation and conditioning were the cause of the cure. None of the monkeys were cured, ruling out this method. Two other leukemia patients with HIV also received transplants, but from donors without the CCR5 mutation. It initially appeared as if they had been cured, the virus eventually returned. While the treatment did not completely cure the patients, the transplants likely helped to reduce the amount of HIV in their bodies.

The conclusion? No definitive answer was reached, but the possibility of conditioning being a cure for HIV was eliminated. Graft versus host disease and the CCR5 mutation in Brown’s donor are still possibilities for a cure for HIV.

The importance of the CCR5 protein Chemokine Receptor 5 is a membrane receptor protein found on human immune cells. It binds specific chemical signals and recruits other immune cells. The protein is also an HIV co-receptor. It allows the initial docking of the HIV virus onto T-cells and subsequent infection. Approximately 15-20% of the northern European population is heterozygous for the 32 base pair deletion in the CCR5 gene, and therefore resistant to HIV. 1% of this population is homozygous for this mutation, and also resistant to HIV.

How the mutation affects the protein The deletion of the 32 base pairs codes for eleven amino acids midway through the gene, changing the translation reading frame. The protein translated from the gene is truncated due to the out-of-frame STOP codon 31 codons after the deletion site. The protein produced by the CCR5 mutant gene is non-functional and therefore does not support HIV infection.

Current genome editing for a cure for HIV Making the host cells resistant to HIV may provide a functional cure for infected individuals. Using an engineered nuclease (such as a zinc finger nuclease) and targeting the CCR5 gene in HIV patients to inactivate the CCR5 protein will make the patient’s T-cells resistant to further infection. A zinc finger nuclease that is targeted to disrupt the CCR5 gene has been developed. This approach is currently being tested in a Phase 2 clinical trial with HIV/AIDS patients.