Download The Berlin Patient and CCR5

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.