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HIV Re-emerges in Boston Bone Marrow Transplant Patients


Two bone marrow stem cell recipients who had undetectable HIV according to the most sensitive tests for months after an experimental antiretroviral therapy (ART) interruption have experienced viral rebound and had to restart treatment, frustrating hopes for a functional cure, according to a report at the 6th International Workshop on HIV Persistence during Therapy last week in Miami.

Timothy Henrich and Daniel Kuritzkes from Brigham and Women’s Hospital first reported at the 2012 International AIDS Conferencethat 2 Boston men with HIV who had received donor stem cell transplants to treat lymphoma had no detectable traces of the virus.

Unlike the Berlin Patient, Timothy Brown, these patients received donor stem cells that were susceptible to HIV infection. Brown's donor had a double CCR5-delta-32 mutation, meaning those stem cells did not express the CCR5 co-receptor that most strains of HIV use to enter cells. Brown, who had leukemia, received an intensive chemotherapy and radiation conditioning regimen to kill off his diseased immune cells so that the donor stem cells could reconstitute a new immune system. He stopped ART at the time of transplantation and remains free of viable HIV 6 years later.

While the Boston patients received normal stem cells, they themselves were CCR5-delta-32 heterozygous, meaning they had a single copy of the protective mutation. In contrast to the potent chemotherapy Brown received, these men used a milder conditioning regimen and were able to stay on ART throughout the transplant process. After maintaining undetectable HIV according to the most sensitive tests for a few years, they underwent analytic ART interruption with frequent monitoring.

At the International AIDS Society this past summer, Henrich reported that the men continued to have undetectable plasma HIV RNA as well as undetectable integrated HIV DNA in peripheral blood mononuclear cells after 7 and 15 weeks off treatment. This finding raised hopes that some aspect of the stem cell transplant process -- other than resistant donor cells, which is difficult to replicate -- might lead to a functional cure, or the ability to maintain viral suppression without disease progression in the absence of ART.

However, as first described last week in the Boston Globe, Henrich reported at the Persistence Workshop that HIV had come back in both men. The first patient showed signs of HIV re-emergence in August, just a month after the IAS conference. The other, who opted to stay off ART, continued to appear HIV-free for 8 months, at which point he too experienced viral rebound. Both men have since restarted antiretroviral treatment and are doing well.

This re-emergence, Henrich said, indicates that the virus is able to hide in reservoirs in the body where researchers have difficulty finding it using existing tools. He noted that it is still unclear what led to the prolonged post-transplant suppression, or why one man was able to hold off its return significantly longer than the other.

As described in an abstract presented at the Miami meeting, Henrich's team used data from the 2 men in a mathematical model to estimate the residual latent reservoir of virus in host cells, in an effort to predict how many infected cells may remain after stem cell transplantation and how long patients should be monitored after ART interruption. After 8 and 15 weeks off therapy, "there is high probability that the patients’ total reservoir sizes are less than 15,000 and 6000 cells, respectively," they concluded. "Residual latent reservoirs may be present, but at levels orders of magnitude below the limit of detection of experimental assays necessitating other methods to estimate viral rebound probabilities and times."

Henrich's team has not yet completed their analysis of these patients, and are expected to present further details at the Conference on Retroviruses and Opportunistic Infections (CROI) next March in Boston.

While these results are disappointing, cure researcher Steven Deeks from the University of California at San Francisco told the Globe than the Boston patients "dramatically advanced the cure research agenda."



T Henrich. Challenges and Strategies Towards Functional Cure: How Low Do You Need To Go. 6th International Workshop on HIV Persistence during Therapy. Miami, December 3-6, 2013. Abstract 45.

T Henrich, E Hanhauser, L Harrison, et al. CCR5-delta-32 Heterozygosity and HIV-1 DNA Reservoir Size in Individuals on Suppressive Antiretroviral Therapy. 6th International Workshop on HIV Persistence during Therapy. Miami, December 3-6, 2013. Abstract 94.

T Henrich, AL Hill, E Goldstein, et al. Mathematical Modeling of HIV-1 Latent Reservoir Dynamics Following Hematopoietic Stem Cell Transplantation. 6th International Workshop on HIV Persistence during Therapy. Miami, December 3-6, 2013. Abstract 130.

Other Source

K Lazar. HIV virus returns after cure hope rose. Boston Globe. December 6, 2013.