By Diane Krause, MD, PhD
2009-05-01
Dr. Krause indicated no relevant conflicts of interest.
Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem cell transplantation. N Engl J Med. 2009;360:692-8.
In this manuscript, Hütter, et al. from Berlin reported that
allogeneic peripheral blood stem cell (PBSC) transplantation from a
donor who is resistant to HIV infection confered resistance to HIV in
an already HIV-positive recipient. In order to follow the events
leading to this transplant, one needs to understand the patient’s HIV
and leukemia status and the genomic variants that confer resistance to
HIV infection.
The 40-year-old male was diagnosed with leukemia (AML M4 with normal
karyotype) and was successfully treated at first, but he relapsed after
seven months. Allogeneic PBSC was then performed. In the absence of an
appropriately matched sibling donor, a matched unrelated donor was
sought.
At the time of AML diagnosis, the patient had been HIV-positive for
10 years and had been on highly active antiretroviral therapy (HAART)
with no detectable HIV in the blood. During his first round of
induction chemotherapy, because of hepatotoxicity and renal failure,
HAART was discontinued for four months, during which his HIV RNA level
increased to 6.9 x 103/microliter. When HAART was reinitiated, the viral load was again undetectable.
The investigators, under the leadership of Drs. Wolf K. Hofmann and
Eckhard Thiel, screened HLA-matched unrelated donors for potential
resistance to HIV and found that one of 62 donors tested was homozygous
for the delta 32 (∆32) variant of CCR5, which confers resistance to R5
HIV variants. This is consistent with the frequency of the ∆32 allele,
which is 5 percent to 15 percent in the Northern European white
population. This allele is rare in people of Asian and African descent.
CCR5 is expressed on T cells, macrophages, and dendritic cells.
While CD4 is a receptor for all HIV, different HIV-1 variants require
different co-receptors for cell entry. CCR5 and CXCR4 are the
coreceptors for HIV-1 R5 and HIV-1 X4 isolates, respectively. Genetic
variants of CCR5 and CXCR4 have been identified that confer resistance
to HIV. Homozygosity for deletion of a 32-basepair sequence in CCR5
leads to expression of nonfunctional receptors, preventing HIV-R5
entry.
The patient underwent allogeneic transplantation
with appropriate immunosuppression. HAART was discontinued.
Approximately one year later, the patient relapsed and received a
second transplant from the same donor. When this paper was written, the
patient had been in remission for 20 months and had an undetectable
viral load without HAART. His T-cell count was normal, and the T cells
were donor-derived.
It is not clear what the long-term prognosis is for the patient. At
the time of AML diagnosis, the patient had been infected with both
HIV-R5 and HIV-X4 variants. Although it is not clear why the HIV-X4
variant is undetectable post-transplantation, it is likely that the
patient still harbors the virus.
This case is proof of principle that allogeneic
transplantation with donor cells resistant to HIV infection can be used
to treat HIV infection, though the severity of such treatment precludes
widespread clinical use given the effectiveness of HAART. Several
pharmaceutical companies are developing inhibitors that block CCR5
interaction with HIV. The findings reported here strongly suggest that
these newer anti-HIV drugs will be effective in patients even after HIV
infection has already occurred.
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