Back HIV Treatment Search for a Cure ICAAC 2013: CD4 Cell Gene Therapy May Enable Functional Control of HIV Off Treatment

ICAAC 2013: CD4 Cell Gene Therapy May Enable Functional Control of HIV Off Treatment


Two people whose CD4 T-cells were modified to make them resistant to HIV experienced substantial CD4 cell gains and were able to maintain viral suppression after interruption of antiretroviral therapy (ART), according to a late-breaker presentation at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) this week in Denver.

Sangamo BioSciences has developed a technique (dubbed ZFP Therapeutic) that uses a zinc finger nuclease to cut out the gene in CD4 cells that controls expression of the CCR5 co-receptor on the surface of cells. CCR5 is one of the gateways most types of HIV use to enter cells.

People with a naturally occurring genetic mutation known as CCR5-delta-32 -- present in about 10% of people of European descent -- do not produce this co-receptor. Individuals with 2 copies of the mutation (1 inherited from each parent) may be elite controllers who maintain undetectable viral load without treatment, while those with a single copy may have lower than normal virus levels.

Researchers have attempted to replicate this natural phenomenon as a potential strategy for curing HIV. The Berlin Patient, who received stem cell transplants to treat leukemia from a bone marrow donor with the double CCR5-delta-32 mutation, appears to be free of HIV several years after stopping ART.

The zinc finger technique aims to produce the same effect using "molecular scissors" to disrupt the normal CCR5-producing gene in the chromosomes of T-cells -- or, ultimately, the hematopoietic stem cells that give rise to all immune cells. A portion of CD4 cells are collected through apheresis, treated with the zinc finger protein in a lab, and the modified cells -- known as SB-728-T -- are returned to the patient.

Researchers have studied the technique in several small cohorts in Phase 1/2 trials. As previously reported, the procedure is generally well tolerated and modified SB-728-T cells appear safe, with no notable safety concerns to date.

SB-728-T cells engrafted, multiplied, and distributed themselves like normal T-cells. Most participants experienced substantial increases in CD4 cells -- including some individuals who not previously achieved adequate immune recovery despite viral suppression on ART -- and gains have been maintained up to 3 years.

Another study presented as a poster at this year's ICAAC showed reduction of the viral reservoir in these earlier cohorts, as indicated by a median 0.6 log decrease in HIV DNA in peripheral blood T-cells at 12 months.

But the real test is whether the modified CD4 cells will be able to resist infection, which can only be determined by doing a careful analytic treatment interruption. Researchers at the University of Pennsylvania previously described one SB-728-T recipient who was able to maintain viral suppression during a 12-week treatment interruption, providing proof-of-concept.

At ICAAC Dale Ando, Sangamo's Chief Medical Officer, reported results from a cohort of 7 people who were CCR5-delta-32 heterozygous, meaning they carry 1 copy of the natural mutation and 1 copy of the normal CCR5-producing gene (Cohort 5/SB-728-902). In theory, it should be easier for gene therapy to produce T-cells completely lacking CCR5 (known as biallelic knockout) if nature has already done half the job.

The study included five 5 men and 2 women. All were white and ages ranged from 32 to 59 years. They had been HIV positive for 2 to 24 years. All were on stable ART with undetectable viral load and current CD4 counts of least 500 cells/mm3 (range 561-800 cells/mm3), but nadir or lowest-ever levels reached as low as 88 cells/mm3. Viral set-points ranged from approximately 3600 to 245,000 copies/mL.

Each participant received a single SB-728-T infusion ranging from 9 to 20 billion cells, with approximately 25% cell modification on average. Once infused, biallelic modification was achieved in about 3% of peripheral blood CD4 cells, Ando said.

At 8 weeks after the infusion patients began a planned 16-week ART interruption. The interruption continued until CD4 count fell below 350 cells/mm3 or HIV RNA viral load rose above 100,000 copies/mL for 3 consecutive weekly measurements. At the end of the planned interruption, people who still had undetectable viral load could remain off treatment until these thresholds were reached.


  • As seen in earlier cohorts, circulating CD4 cells shot up from the baseline level in the week after the infusion, with 1 person approaching 2500 cells/mm3.
  • CD4 levels then stabilized at closer to normal levels, which were sustained for up to a year.
  • 3 participants were classified as responders, meaning they re-suppressed viral load after stopping treatment (at least a 1 log drop during treatment interruption); these included both the women in the study as well as the youngest patient.
  • 3 participants were classified non-responders, and the final participant was 12 weeks into an ongoing interruption and not further evaluated.
  • Among the responders, 1 person (participant 04-502) had a jump in viral load after stopping ART, which was then suppressed to undetectable from week 11 to 19; treatment interruption is ongoing.
  • Another person (01-509) had transient undetectable viral load and also remains off treatment.
  • The third responder (10-503) completed a 20-week treatment interruption with a 1 log decrease in viral load from her peak level while off ART.
  • 2 non-responders (01-506 and 09-508) resumed ART after their viral load rose and stayed above 100,000 copies/mL; the third had no change in viral load during a 16-week interruption.
  • All responders had low viral set-points (3600-4800 copies/mL) compared with non-responders (50,000-245,000 copies/mL).
  • Responders also had lower HIV DNA levels in peripheral blood T-cells (maximum 122 copies) than non-responders (maximum 931 copies).
  • Changes in viral load correlated with levels of double-knockout CD4 cells, with a higher proportion of biallelic modified cells predicting a lower level of virus.

"This is the first study to demonstrate that functional control of HIV by the immune system may be possible by providing a population of CD4 T-cells made HIV resistant by biallelic modification of CCR5 (SB-728-T)," the researchers concluded. "The data demonstrate that the level of engrafted CCR5 modified, HIV protected, CD4 T-cells and the magnitude of the HIV reservoir are important factors in the functional control of HIV viremia during treatment interruption."

"The data presented today demonstrate that a single infusion of SB-728-T can lead to profound suppression of viral load in the blood and sustained functional control of the virus," Ando summarized in a press release issued by Sangamo. "This is the first evidence that sustained functional control of HIV in the absence of ART is possible."

These findings support moving forward with a new cohort of people without the CCR5-delta-32 mutation -- like the vast majority of people with HIV -- who will undergo conditioning with the chemotherapy drug cyclophosphamide (Cytoxan) to get rid of some normal HIV-susceptible CD4 cells to make room for the new SB-728-T HIV-resistant cells.

Session moderator Pablo Tebas, who studied the aforementioned University of Pennsylvania patient, said these results are a "strong signal" that this gene therapy approach is effective. He suggested that an increase in viral load after stopping ART may be a necessary part of procedure, as resurgent virus may kill off normal CD4 cells and therefore select for the modified resistant cells.



D Ando, J Lalezari, G Blick, et al. Functional control of viremia in CCR5-Δ32 heterozygous (Δ32HZ) HIV+ subjects following adoptive transfer of zinc finger nuclease CCR5 modified autologous CD4 T-cells (SB-728-T). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-1464c.

J Zeidan, G Lee, J Lalezari, et al.Host immune environment significantly impact the level of CD4 reconstitution and the effects on latent reservoir in HIV subjects receiving ZFN CCR5 modified CD4 T-cells (SB-728-T).53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-674.

Other Source

Sangamo BioSciences. Sangamo BioSciences Announces Presentation of Clinical Data Demonstrating Functional Control of Viremia in HIV-Infected Subjects treated with SB-728-T. Press release. September 12, 2013.