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09/18/2013

The Search for the Cure— A New Study at ICAAC 2103


While contemporary ART can continuously suppress HIV to very low levels, it does not eliminate the latent reservoir which can rekindle HIV infection if ART is discontinued. Finding alternatives to life-long ART is an active area of HIV research. Treatments that aim to maximally suppress HIV replication, then purge the latent reservoir are pursuing a “sterilizing cure” in which all replication competent HIV is eliminated. In a alternate approach, a ‘functional cure” would be achieved if HIV replication was limited by a stimulated host immune response or by genetic engineering of CD4 cells to induce resistance to infection, even if low level HIV replication and the latent reservoir remained. To that end, scientists at Sangamo BioScience and collaborators reported on the effects of adoptive transfer of CCR5-modified autologous T-cells. Based on a previous observation of greater success in creating bialleleic deletion of the CCR5 gene, the current study was carried out in 10 HIV-infected subjects heterozygous for the CCR5Δ32 deletion. All were taking fully suppressive ART. Eight weeks after receiving and infusion of genetically modified T-cells, ART was interrupted.

Three subjects were excluded from the analysis after being found to harbor X4 virus. The seven remaining participants, all had viral rebound during treatment interruption. One patient resuppressed HIV RNA to undetectable levels and has remained undetectable for 8 weeks in an ongoing ART interruption. Another patient transiently resuppressed virus to undetectable levels and has continued off ART with viremia hovering in the 1,000 copy range for nearly 11 months. The other patients all had high level viral rebound, although one had not yet finished the planned 16 week treatment interruption. As seen with other patients treated with this technology, following infusion of the genetically modified cell pool, CD4 lymphocyte counts rose dramatically, increasing by >1000/mm3 at one month, declining slowly thereafter but remaining elevated over baseline at one year.

Many questions remain about this therapeutic approach. Since very few patients have been treated and there is no control group, it is hard to tell if the few patients who controlled viremia did so as a result of the intervention or if these might be either spontaneous or post-treatment controllers. To be an alternate to ART, treatment would need to induce viral suppression of comparable magnitude and durability in a high percentage of recipients, which has not yet been demonstrated. The rise in CD4 cells is impressive but only a small fraction these cells contain the genetic modification.The mechanism driving expansion of unmodified T-cells and their functional characteristics need to be determined. Also, the long-term safety of genetically modified T-cell infusions needs to be established.

Reference:
Ando A, Lalezari J, Blick G, 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 ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1464c.


Source: Reporting from Denver for the PRN News: David H Shepp, MD