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CROI 2012: Zinc Finger HIV Gene Therapy Moves Ahead

Further good news was presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this month in Seattle regarding SB-728-T, the Sangamo zinc finger nuclease HIV gene therapy currently in Phase 2 development.alt

Pablo Tebas from the University of Pennsylvania updated conference-goers on new data from 2 open-label cohorts previously presented at CROI 2011 and ICAAC 2011. The data bolster the zinc finger nuclease concept as an HIV therapy and give a green light for moving forward in expanded trials.

Participants in these studies donate blood cells in a procedure called apheresis. CD4 cells are extracted and processed with the zinc finger nuclease to disrupt expression of the CCR5 co-receptor, which is necessary for many strains of HIV to enter cells. The altered SB-728-T cells -- made resistant to HIV -- are allowed to multiply in the laboratory and then re-infused back into the same participant.

So far, in small cohorts from Philadelphia and San Francisco, the concept has proven safe, and the modified CD4 cells were shown to engraft and persist in the body. "The cellssurvive, seem to behave normally, and go to places they are supposed to go," Tebas explained at a CROI press conference about approaches to a cure for HIV.

Tebas presented further data on participants given 1 infusion of 5 to 30 billion SB-728-T cells who have been followed up to 700 days thus far. These participants included 6 immunological responders with CD4 cell counts > 450 cells/mm3 and 15 immunological non-responders with CD4 counts < 500 cells/mm3.

All but 2 were men and the average age was approximately 47 years. The immunological responders had been HIV positive for 12 years on average and had a mean baseline CD4 count of about 920 cell/mm3. The non-responders had been positive for 18 years on average and had a mean CD4 count of about 330 cells/mm3.

One remaining question was whether HIV RNA levels would be affected by SB-728-T cells. To show this, participants stopped antiretroviral therapy with careful monitoring during the trial, known as analytic treatment interruption.

UPenn also developed a sensitive digitized PCR assay that allows precise quantification of integrated proviral DNA (HIV genetic material integrated into host cell chromosomes). This allowed investigators to analyze replenishment of the viral reservoir inside CD4 cells during analytic treatment interruptions.


  • A single infusion of SB-728-T is safe and well tolerated.
  • There have been no serious adverse events except 1 case of arthritis that resolved after a few days, most likely a reaction related to the transfusion.
  • After about 1 year, dramatic increases in total CD4 cells were sustained in both groups.
  • Modified cells engrafted, expanded, and persisted for more than 1 year in the blood and gut-associated lymphoid tissue.
  • Participants' CD4:CD8 ratios normalized.
  • Increases in IL-2, IL-7, and IL-15 were seen, thought to be associated with expansion of CD4 cells.
  • In the immunological responder group, all participants saw an initial increase in HIV viral load and a subsequent drop during a 12-week analytic treatment interruption.
  • 1 participant who was later found to be CCR5-delta 32 heterozygous had an initial increase in viral load and then dropped to undetectable during a 12-week treatment interruption.
  • 6 patients analyzed with the sensitive PCR assay were shown to have modest increases in integrated DNA during treatment interruption, but levels returned to baseline a few weeks after resumption of antiretroviral drugs.

Further research into SB-728-T zinc finger therapy is being conducted in 2 clinical trials for participants who are CCR5-delta 32 heterozygous. These people have 1 copy of an uncommon natural genetic mutation that produces T-cells lacking CCR5. As Tebas explained, "nature did half the job" for the heterozygous participant who achieved undetectable viral load during treatment interruption in the current study.

In addition, a chemotherapeutic conditioning agent will be used in 1 infusion prior to the SB-728-T infusion to make way for more modified cells.

Various approaches to curing HIV will "probably have to be used in combination," Tebas suggested. "This might be one of the strategies we will use the future."



C June, P Tebas, D Stein, et al. Induction of Acquired CCR5 Deficiency with Zinc Finger Nuclease-modified Autologous CD4 T Cells (SB-728-T) Correlates with Increases in CD4 Count and Effects on Viral Load in HIV-infected Subjects.19th Conference on Retroviruses and Opportunistic Infections. Seattle, March 5-8, 2012. Abstract 155.