Strategies in fighting AIDS

Few days ago, I blogged about how Perez et al made use of zinc finger nucleases as DNA scissors to get rid of the CCR5 allele within the CD4 T cell, which would confer resistance to the HIV virus. Yet another method exists, which allows gene editing to be made to the CCR5 gene. This is achieved using single-stranded oligonucleotides. These single-stranded oligonucleotides were shown to induce site-specific alterations by activation of DNA repair pathways.

Oligonucleotide-based gene editing has been suggested as an approach to correct genes resulting in neuro-muscular disorders (Bertoni, 2005). Other than single stranded DNA oligonucleotides, DNA/RNA hybrid molecules and double stranded DNA molecules of 100 - 1000 base pairs can be used. The use of microinjection technology allow for the introduction of these genome-altering molecules into the stem cell (Davis).

Unlike current therapeutic approach to correct the defective gene, the trick is to make the CCR5 gene defective which is the opposite, and in doing so, generate a population of HIV-resistant CD4 T cells.

Citations
1) Bertoni C. Oligonucleotide-mediated gene editing for neuromuscular disorders. Acta Myol. 2005 Dec;24(3):194-201.

2) David BR. Genome editing - Its promise and limitations for gene therap. At: http://www.pasteur.fr/applications/euroconf/geneandcelltherapy/22_Davis_abstract.pdf

Cure for AIDS

The successful transplant of bone marrow by Dr Gero Huetter and followed by the patient's showing no signs of HIV infection might provide some insights into the road to eradicating HIV.

In 2002, it was reported that the Great Ormond Street Hospital successfully attempted gene therapy of a 'bubble' child, who is obviously suffering from SCID. Earlier in June this year, Perez et al demonstrated HIV resistance in CD4 T cells by transciently expressing CCR5 zinc finger nuclease to induce genetic disruption of the CCR5, which provides stable and heritable resistance to HIV virus (Perez et al, 2008). CCR5 is known to be a mediator in the entry of a HIV virus to a T cell. Those with a mutation in the CCR5 are known to be resistant to HIV. The CCR5 zinc finger nuclease provides permanent disruption of the CCR5 allele. Advances have also been made in "gene editing" techniques, which uses zinc finger nucleases.

Perhaps, a possible approach to curing AIDS would be to introduce the zinc finger nucleases to bone marrow cells via gene therapy techniques, transciently expressing these nucleases in order to disrupt the CCR5 alleles. Without the functional CCR5, these altered cells which will be transplanted back into the bone marrow would generate new generations of HIV resistant CD4 T cells.

Citations

1) Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008 Jul;26(7):808-16. Epub 2008 Jun 29