All Things Stem Cell

Recently, a patient with leukemia and human immunodeficiency virus (HIV) had apparent remission of both after stem cell transplants (Hütter et al., 2009). As discussed earlier, hematopoietic stem cells have been used in transplants to rescue patients with leukemia, but this method has not previously been as successful for treating HIV, the virus that causes acquired immunodeficiency syndrome (AIDS).

Once in the body, HIV primarily attacks the immune system, such as T cells, though some individuals have T cells that are naturally resistant to HIV infection. Over a decade ago, this resistance was found to be due to a mutation in a receptor that is normally on the cell surface of T cells, called chemokine receptor 5 (CCR5) (Liu et al., 1996). CCR5 is a chemokine receptor, meaning it normally binds and receives signals from chemokines, which are molecules cells can release and receive to cause an immune system response. CCR5 is thought to normally be involved in causing a response to infection, though its exact function is not fully understood. HIV normally interacts with CCR5 to gain entry into the target T cell, but some individuals have a mutation in the CCR5 gene, specifically a 32 base-pair deletion, that renders the resultant receptor completely nonfunctional and consequently prevents HIV from being taken into these cells (Liu et al., 1996).

The T cell membrane (shown as the purple, semicircle double line) allows entry of HIV (in pink) into the cell through multiple cell receptors anchored on the membrane, including CCR5.

Looked upon as a potential cure for HIV, the CCR5 gene and its deletion allele (CCR5-∆32) have been much studied since their discovered involvement in HIV infection. Approximately 5% to 14% of Europeans have the CCR5-∆32 allele, but it is absent in African, East Asian, and Native American populations. The mutation is thought to have arisen over 5000 years ago, casting aside theories that it was caused by positive selection during the bubonic plague (Sabeti et al., 2005). While heterozygous CCR5-∆32 individuals (having only one copy of CCR5-∆32) lessen HIV infection, individuals homozygous for CCR5-∆32 confer very high HIV resistance, though they make up approximately only 1% of the European population (Hütter et al., 2009; Liu et al., 1996; Lederman et al., 2006). Homozygous individuals have no apparent health problems. Based off of the known resistance the CCR5-∆32 mutation creates, anti-HIV drugs have been created that bind the CCR5 receptor, preventing HIV binding (Lederman et al., 2006).

A few weeks ago it was reported that a 40-year-old Caucasian patient with leukemia and HIV underwent hematopoietic stem cell transplants using peripheral blood from a donor homozygous for CCR5-∆32 and, over 20 months later, not only has the leukemia gone into complete remission, but the patient has no HIV detectable in his body either (Hütter et al., 2009). Before the transplant, the patient was on highly active antiretroviral therapy (HAART), the combined use of several antiretroviral drugs that has been found most effective in decreasing mortality rates caused by AIDS (Palella et al., 1998). The patient ceased taking HAART immediately prior to undergoing chemotherapy, due to the toxicity of the powerful drugs, but after the following stem cell transplant he has not since resumed the therapy and there have been no detectable signs of HIV in his system. The CCR5-∆32 homozygous hematopoietic stem cells appear to have replaced his irradiated immune system with CCR5-∆32 homozygous, HIV-resistant cells. Previously, hematopoietic stem cell transplants have been attempted to cure patients with both HIV and leukemia with some success (Sorà et al., 2001; Huzicka, 1997), but none used CCR5-∆32 homozygous donors.


While this is quite the success story, a bone marrow transplant is still usually a riskier prospect than using HAART, though this could change with additional research. This treatment should be repeated in other patients to confirm the validity of the technique, and it must also be taken into consideration that some HIV strains do not access T cells using CCR5, but other surface receptors instead (Lederman et al., 2006). A potentially appealing application of the knowledge gained from this study is to use gene therapy to create CCR5-∆32 homozygous cells to confer HIV resistance, which should become a more viable technique as the field of gene therapy progresses.

References

Hütter, G., Nowak, D., Mossner, M., Ganepola, S., Müßig, A., Allers, K., Schneider, T., Hofmann, J., Kücherer, C., Blau, O., Blau, I. W., Hofmann, W. K., and Thiel, E. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. N. Engl. J. Med. 2009. 360:692-8.
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Huzicka, I. Could bone marrow transplantation cure AIDS? Med. Hypotheses. 1999. 52:247-57.
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Lederman, M. M., Penn-Nicholson, A., Cho, M., and Mosier, D. Biology of CCR5 and Its Role in HIV Infection and Treatment. JAMA. 2006. 296:815-826.
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Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., and Landau, N. R. Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection. Cell. 1996. 86:367-77.
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Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J., and Holmberg, S. D. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med. 1998. 338:853-60.
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Sabeti, P. C., Walsh, E., Schaffner, S. F., Varilly, P., Fry, B., Hutcheson, H. B., Cullen, M., Mikkelsen, T. S., Roy, J., Patterson, N., Cooper, R., Reich, D., Altshuler, D., O’Brien, S., and Lander, R. S. The Case for Selection at CCR5-Δ32. 2005. PLoS Biol. 3(11): e378.
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Sorà, F., Antinori, A., Piccirillo, N., De Luca, A., Chiusolo, P., Cingolani, A., Laurenti, L., Rutella, S., Ortona, L., Leone, G., and Sica, S. Highly active antiretroviral therapy and allogeneic CD34(+) peripheral blood progenitor cells transplantation in an HIV/HCV coinfected patient with acute myeloid leukemia. Exp. Hematol. 2002. 30:279-84.
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Original “HIV T cell Entry” image from the Wikimedia Commons and redistributed freely as it is in the public domain.

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