Hütter G, Nowak D, Mossner M, et al. . N Engl J Med. 2009;360:692-8.
Long-term control of HIV by CCR5 Delta32/Delta32 stem cell transplantation
 

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.

Competing Interests

Dr. Krause indicated no relevant conflicts of interest.