ABSTRACT & COMMENTARY
Gene-Modified CD4+ T-cells Infused in HIV Patients may be a Promising Treatment
By Dean L. Winslow, MD, FACP, FIDSA
Clinical Professor of Medicine and Pediatrics Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, is Associate Editor of Infectious Disease Alert
Dr. Winslow is a consultant for Siemens Diagnostic
SYNOPSIS: Autologous CD4+ T-cells modified to delete CCR5 by Zinc-finger nuclease (ZFN) were infused into 12 HIV-infected patients. Cells survived in the circulation of patients and provided some control of viral replication and immune reconstitution after interruption of antiretroviral therapy.
SOURCE: Tebas P, et al. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. N Engl J Med 2014; 370: 901-910.
Twelve patients with aviremic stable HIV infection receiving antiretroviral therapy had lymphocytes harvested, had ex-vivo modification of the CCR5 genes performed in the CD4+ T-cells using ZFN, then had approximately 10 billion of those CD4+ cells reinfused (11-28% of which were shown to have undergone CCR5 modification). 6 patients underwent interruption of HAART 4 weeks after the infusion of the T-cells. Preinfusion CD4 counts were a median of 448 cells/uL At 1 week post infusion, the median total CD4 count was 1517/uL and median CCR5-modified CD4 count was 250/uL, constituting 13.9% of total circulating CD4 cells. The mean half-life of the genetically-modified CD4 cells was estimated to be 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5- modified cells (−1.81 cells per day) was significantly less than the decline in unmodified cells (−7.25 cells per day) (P = 0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. Infusion of cells was generally well-tolerated with only one patient experiencing a transfusion reaction.
In the mid-1990's the chemokine receptors, CCR5 and CXCR4 were identified as the major co-receptors for HIV on CD4+ T-cells. It was later demonstrated that the relatively common (in patients of Northern European genetic origin) 32 base pair deletion in CCR5 when present in homozygotes conferred almost complete resistance to infection with HIV. Heterozygous individuals who possessed one copy of this deletion per cell were often "long term nonprogressors" who maintained relatively preserved CD4 counts in the absence of antiretroviral therapy. Maraviroc, a small molecule, orally bioavailable inhibitor of CCR5/HIV-1 binding has demonstrated clear antiretroviral activity and is effective (as part of a HAART regimen) in the treatment of HIV infection in individuals who are infected with CCR5-tropic HIV. Finally, the "Berlin patient" (a man with chronic HIV infection who developed acute leukemia and received a bone marrow transplant from a homozygous CCR5 delta 32 donor) has had undetectable plasma and lymph node HIV-1 RNA and proviral DNA more than 4 years post-transplantation and off antiretroviral therapy. 1,2
While the trial reported here does not represent a "cure" for HIV infection, the success in providing short-term immune reconstitution and partial suppression of HIV replication without HAART is exciting and may, eventually prove to be clinically beneficial. In addition, the use of other novel Zinc finger nucleases may prove to be useful in the treatment of other infections or non-infectious genetic diseases.
- Hütter G, et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009;360:692-8.
- Allers K, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011;117:2791-9.