2015 American Society of Gene and Cell Therapy Annual meeting in New Orleans, LA - Highlights - Long-term engraftment of zinc finger modified T-cells in HIV infection

Sangamo Biosciences (Richmond, CA, USA) presented novel clinical data regarding the SB-728-T-cell program for viral load control in chronic HIV infection. In this open-label phase 1 clinical trial, nine patients with low CD4+ T cell counts (200-500 cells/mm3) received 10-30 billion autologous, zinc finger nuclease modified CCR5 knockout T-cells.
Interestingly, modified T-cells were still detectable in the circulation after 3 years and generated long-lived T-memory stem cells. The authors demonstrated a sustained increase of CD4+ T cell counts in all treated subjects. T-memory stem cell count correlated with the decay of viral load.

Taken together, the SB-728-T-cell infusion unexpectedly resulted in very long term T-cell reconstitution, owing to the transformation of the zinc-finger edited T-cells to long lived memory stem cells. The program is now in Phase II, while a similar hemopoietic stem cell approach is already in phase I.

Combat HIV via the CRISPR system

With permission from NPG

It look like a real "cure" is underway for AIDS, a disease used to be one of the most fearsome one of the modern era. Just recently, Sangamo Biosciences received FDA approval to carry out clinical trials with zinc-finger nucleases to knock out the virus receptor on normal human hemopoietic stem cells. Now, it seems that the bacterial defense system, the CRISPR, could also be utilized to combat viral infection in human cells. In a recent paper, a group from La Jolla, CA developed a CRISPR strategy to attack invading HIV, making the antiviral tool expressing cells resistant to infection.

The authors first transduced 293T cells with replication incompetent lentiviruses carrying a GFP as a target for CRISPR. Not surprisingly disruption of GFP was readily detectable in Cas9/gRNA expressing cells. Novelty here is that it seems Cas9 can target the pre-integration viral genome, i.e. the human chromosomal environment is not required for action (as assayed by non-integrating lentiviruses). This is quite plausible, since the original bacterial CRISPR system indeed inactivates viral and plasmid DNA sequences, which have not been integrated into the host. Interestingly, CRISPR was able to be active in a high copy number system, projecting its usefulness in transgene animal models, where multiple copies of the transgene is present.

Also not surprisingly CRISPR was able to target HIV viral sequences in 293T.CD4.CCR5 cells, latently infected human T cell lines and differentiated human pluripotent stem cells. However, primary human T-cells were conferred only partially resistant to HIV infection.

This study is in correlation with other studies demonstrating antiviral effect of CRISPR against hepatitis B virus, papillomavirus, herpes simplex virus. I'm not sure how these findings are translatable to human clinical trials.

Full text of the paper here: Liao HK, Gu Y, Diaz A, Marlett J, Takahashi Y, Li M, Suzuki K, Xu R, Hishida T, Chang CJ, Esteban CR, Young J, Izpisua Belmonte JC. Use of the CRISPR/Cas9
system as an intracellular defense against HIV-1 infection in human cells. Nat Commun. 2015 Mar 10;6:6413. doi: 10.1038/ncomms7413.