A letter published yesterday in the New England Journal of Medicine describes the outcome of a recent attempt to repeat the HIV cure achieved in Timothy Brown. An HIV-positive individual requiring stem cell transplantation for the treatment of cancer (anaplastic large-cell lymphoma) was matched with a donor homozygous for the CCR5Δ32 mutation, which renders cells resistant to CCR5-tropic HIV. Pre-transplant analyses indicated that the majority of HIV in the individual was CCR5-tropic, but there was also evidence of HIV strains capable of entering cells via the CXCR4 (X4) receptor.
Antiretroviral therapy (ART) was interrupted during the transplantation procedure, but restarted afterward due to a viral load rebound to 93,390 copies. Analysis of the rebounding virus revealed the selection of mutations associated with X4-tropism, consistent with this virus gaining a selective advantage after the transplantation of cells resistant to CCR5-tropic HIV. Viral load was successfully re-suppressed by ART for nearly a year until the individual experienced a relapse of the lymphoma. The relapse necessitated a second ART interruption, leading to a viral load increase to 7,582,496 copies, and the individual died from the cancer shortly afterward. The researchers note the case illustrates that the presence of X4-tropic has the potential to undermine strategies that aim to cure HIV infection by knocking out the CCR5 receptor. The case report also underscores the importance of monitoring HIV tropism in other research studies looking to provide stem cells from CCR5Δ32 homozygous donors to HIV-positive people requiring transplants for the treatment of cancers. Two such studies are ongoing in the US: BMT CTN 0903 and IMPAACT P1107.
The question of why X4 virus did not emerge in Timothy Brown is addressed in an open access paper published in the August 15th issue of Clinical Infectious Diseases. Jori Symons and colleagues report that there was a minority population of HIV present prior to Brown’s transplant that showed evidence of X4 tropism (based on genetic analysis of the viral envelope). However, laboratory experiments revealed that these viruses required the presence of CCR5 in order to gain entry into cells, and could not replicate in cell lines lacking the receptor.
Kordelas L, Verheyen J, Esser S. Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation. N Engl J Med 2014; 371:880-882. August 28, 2014. DOI: 10.1056/NEJMc1405805