therapy that interferes with co-receptors on the surface of T-cells
can protect these cells from HIV infection, representing a potential
first step toward achieving a "functional cure",
researchers reported at the
18th Conference on Retroviruses and
Opportunistic Infections (CROI), taking place this week in Boston.
uses two different surface co-receptors
– CCR5 and CXCR4
– to enter
CD4 T-cells. If the co-receptors are blocked or disrupted, the virus
is unable to enter cells. Two presentations on Monday looked at using
gene therapy to create cells that lack these receptor proteins and
therefore are protected from infection.
Lalezari from Quest Clinical Research in San Francisco and colleagues
used zinc finger nuclease technology developed by Sangamo BioSciences
to disable the gene responsible for producing the CCR5 co-receptor on
work draws upon knowledge gained from 'elite controllers',
a small proportion of HIV-positive people who have a natural genetic
mutation known as CCR5-delta-32. These individuals do not express
CCR5 on their T-cells and are able to maintain undetectable or very
low viral load without antiretroviral therapy.
a man dubbed the "Berlin patient" received two bone marrow
transplants to treat leukaemia from a donor with the delta-32
mutation. His own immune cells were destroyed by chemotherapy to wipe
out the leukaemia, and his immune system was reconstituted with cells
that lacked CCR5. The man stopped antiretroviral therapy, and three
years later researchers are unable to find any trace of HIV.
that bone marrow transplants are not feasible on a large scale,
investigators are exploring other ways to achieve a similar outcome.
phase 1 study included six HIV-positive participants on
antiretroviral therapy. All were men, most were in their early
fifties, and they had been infected for twenty to thirty years. They
had undetectable viral load (< 50 copies/ml) but had not
experienced optimal CD4 cell recovery, having counts within the 200
to 500 cells/mm3 range.
underwent a procedure known as apheresis, in which blood is withdrawn
from the body, T-cells are filtered out, and the rest of the blood is
T-cells were sent to a laboratory where they were activated and
treated with the zinc finger nuclease carried by an adenovirus
vector. The nuclease causes a double-strand DNA break in the CCR5
gene, Lalezari explained, and the repair process permanently disrupts
cells were expanded outside the body and about 25% were successfully
modified. The CCR5-deleted cells
– known as SB-728-T
– were then
frozen, sent back to the study clinics, and re-infused back into the
original patients. Two cohorts received doses of ten and twenty
billion cells; a third cohort, now underway, will receive thirty
apheresis and re-infusion process was safe and generally well-tolerated. Some participants experienced flu-like symptoms, but these
were temporary. No serious adverse events or abnormal lab tests were
observed. "There don't appear to be any safety issues,"
Lalezari said at a press conference discussing the study.
all six participants the altered CD4 cells engrafted, or took up
residence in the body, and proliferated in a manner similar to normal
T-cells. Five of the six experienced significant, sustained increases
in number of CD4 cells, averaging about 200 cells/mm3,
though gains varied widely across patients and over time.
participants also experienced normalisation of the CD4 cell to CD8
cell ratio, which is typically reversed in people with HIV.
90 days, up to 7% of peripheral blood CD4 cells showed the CCR5
deletion. Rectal tissue biopsies revealed that the altered CD4 cells
were distributed to the gut lining like normal T-cells.
observed expansion of CD4 cells was on average three-fold greater
than expected based on the number of infused cells, Lalezari noted.
He acknowledged, however that the alteration procedure involved
activating the cells, which may have contributed to their
one participant who did not respond as well to the treatment had high
levels of antibodies against the adenovirus vector, which may have
made the CCR5 deletion procedure less effective.
results represent a proof of concept that further validates the
Berlin patient findings, Lalezari said, but he cautioned that it is
too early to talk about these results as a cure.
next step will be to test the CCR5 removal procedure in HIV-positive
people with replicating virus to see if re-infusion of altered CD4
cells reduces viral load and confers a clinical benefit. Researchers
will look at treatment-naive individuals who have not yet started
therapy, as well as some treatment-experienced "salvage"
patients who are not responding to current therapy.
hope, Lalezari said, is to provide a reservoir of cells that are
resistant to HIV infection. If the gene therapy technique is
successful, it should confer a significant survival advantage, since
protected cells would continue to proliferate while susceptible cells
would be infected with HIV leading to their early death.