Assessing the impact of chemo and stem cell transplantation on HIV

The success of doctors in Berlin apparently curing a person (the “Berlin patient”) of HIV has stimulated scientists in high-income countries to attempt to do the same. It should be noted that the apparent success of the Berlin researchers might have rested on one or more of the following factors:

• multiple stem cell transplants from a donor whose cells did not have the co-receptor called CCR5, which is needed by HIV to infect cells
• intensive doses of chemotherapy and radiation
• post-transplant the man developed an intense immunologic reaction whereby the transplanted cells attacked his tissues. This type of reaction is called GvHD (graft vs. host disease) and was ultimately controlled with the use of immune-suppressive transplant drugs. However, some researchers suspect that GvHD may have also helped to destroy residual HIV-infected cells.
• the use of transplant drugs may also have played a role by suppressing inflammation and reducing HIV’s ability to infect cells. Since the beginning of the HIV epidemic, researchers have conducted clinical trials of transplant drugs and corticosteroids. Although these drugs are immunosuppressive and it seems counter-intuitive to use them in HIV infection, clinical trials of low doses of these drugs in HIV-positive people suggest the possibility that there may be a benefit to the immune system. This may occur because these drugs reduce excessive inflammation and other immunologic dysfunction incited by the virus.

The protocol used by the Berlin doctors is toxic and caused complications that persisted for several years. Subsequent attempts to replicate their protocol have initially led to several deaths. However, with much caution, researchers are still attempting to effect a cure by making some modifications to the Berlin protocol.

Researchers in Pennsylvania and California have evaluated 10 HIV-positive participants before and after they received intensive chemotherapy for cancer (lymphoma) followed by a transplant of stem cells. Each participant had some stem cells removed prior to chemotherapy and then had them transplanted after their course of chemo was over. These cells were not modified to resist HIV. Participants were taking ART and generally tolerated it during chemo. However, three of them had to interrupt ART because of severe chemo-related side effects.

Technicians developed an in-house viral load test that could detect as little as one copy of HIV RNA in the blood. Using this tool they found that after transplantation, participants had a viral load of about 2 copies/ml.

In one patient, researchers could not detect HIV replication with their ultra-sensitive assay. However, when they analysed his blood with other assays, they found that he had HIV-infected cells (as did all the other participants). Despite being monitored for up to 10 years, the proportion of infected cells in all of the participants did not decline after their transplant.

Why did HIV persist?

Chemotherapy is designed to wipe out rapidly dividing tumour cells. The cells of the immune system that contain latent HIV include a group of cells called “resting CD4+ T cells” by researchers. These cells are not active and chemotherapy might not kill them.

Another possibility is that the stem cells used for transplantation contained some cells that were infected with HIV. Therefore, the transplant could have helped to re-establish HIV.

Based on these results, stem cells harvested from ART users whose viral load is less than 50 copies/ml and then transplanted after chemo are not going to reduce the burden of HIV-infected cells or cure HIV.

—Sean R. Hosein

REFERENCES:

1. Kent SJ, Reece JC, Petravic J, et al. The search for an HIV cure: tackling latent infection. Lancet Infectious Diseases. 2013; in press.
2. Katlama C, Deeks SG, Autran B, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013; in press.
3. Cillo AR, Krishnan A, Mitsuyasu RT, et al. Plasma viremia and cellular HIV-1 DNA persist despite autologous hematopoietic stem cell transplantation for HIV-related lymphoma. Journal of Acquired Immune Deficiency Syndromes. 2013; in press.
4. Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. Journal of Infectious Diseases. 2013; in press.
5. Petz LD, Redei I, Bryson Y, et al. Hematopoietic cell transplantation with cord blood for cure of HIV infections. Biology of Blood and Marrow Transplantation. 2013 Mar;19(3):393-7.
6. Mitsuyasu R. Curing HIV: Lessons from cancer therapy. Current Opinion in HIV/AIDS. 2013; in press.