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Gene therapy studies show potential for HIV control without drugs
Gus Cairns, 2013-03-13 06:50:00
Gene therapy approaches that involve the genetic modification of human haematopoietic stem cells have the potental to engineer HIV control by introducing cells resistant to HIV infection, the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) heard last week.
The proof of concept for this approach to HIV control in humans comes from the case of the 'Berlin patient', who received a bone marrow transplant from a donor with natural resistance to HIV infection. The donor was homozygous for the CCR5 delta 32 mutation, meaning that cells potentially vulnerable to HIV infection would never display the CCR5 receptor necessary for HIV to gain entry to that cell. As a result of complete ablation of the recipient's own stem cells by chemotherapy, his CD4 cells were replaced by cells derived from the donor's CCR5-lacking population. Over three years after the procedure the recipient remains HIV-free without antiretroviral treatment, and has been described as "functionally cured" by physicians.
However, the chance of reproducing this outcome using transfer of donor cells is very low due to the shortage of potential donors who are both HLA-compatible (essential for avoidance of graft-versus-host disease) and CCR5-delta32 homozygous. In any case, the essential elements that contributed to this functional cure are still not fully understood.
The introduction of modified genes into stem cells harvested from a person's bone marrow will be a necessarily individualised treatment, but the costs of gene therapy are likely to come down in the future, and if experimental approaches prove successful in controlling HIV without antiretroviral drugs, gene therapies may deliver a cost-effective form of treatment in the future.
The first human studies of gene therapy have sought to modify the expression of the CCR5 receptor. Sangamo Biosciences is developing a zinc finger nuclease which prevents CCR5 expression; study results have been presented at a number of conferences including ICAAC 2011 and CROI 2013 showing that the procedure is safe and that it results in long-term gains in CD4 cell numbers in people also taking antiretroviral therapy.
Two papers presented at CROI 2013 described the use of modified immune cells that make their own peptides (short chains of amino acids) and act as fusion inhibitors, similar to the drug T-20 (enfuvirtide, Fuzeon). In one experiment these cells, which essentially made their own anti-HIV drug, acted as a treatment or therapeutic vaccine, curbing the viral load of a laboratory virus engineered to be far more virulent than human HIV; in the other, they prevented infection by a similar virus.
In the first study, rhesus monkey stem cells, the progenitors of T-cells and all immune cells, were genetically altered to express a fusion inhibitor peptide called mC46. While not able to prevent infection in monkeys challenged with a highly pathogenic monkey/human SHIV (a laboratory-manufactured virus combining parts of both the human and simian immunodeficiency virus genomes, created for research purposes), it did produce infections characterised by viral loads 2.5 and 3.15 logs lower than in the control group of monkeys.
In another study, human CD4 cells had a fusion-inhibitor peptide called C34 attached to their co-receptors (CCR5 or CXCR4). These were able to resist infection by HIV in the test tube.
Source:1
