Examples of media coverage:
- Researchers Find New Way to Kick Out HIV from Infected Cells– Time, July 21, 2014
- Temple Researchers Snip Out Dormant HIV from Cells– Philadelphia Enquirer, July 22, 2014
- Genome Editing Cuts Out HIV– Scientist, July 21, 2014
- Scientific journal article: RNA-Directed Gene Editing Specifically Eradicates Latent and Prevents New HIV-1 Infection – PNAS, July 21, 2014
- Press release: Temple University Researchers Eliminate the HIV Virus from Cultured Human Cells for First Time – Temple University Health System, July 21, 2014
This story originates from a study published in the scientific journal PNAS on July 21, 2014. The study employed a relatively new technology designed to be able to delete specific genes from the human genome (often likened to scissors snipping out the targeted genes). The researchers assessed whether the approach could delete HIV that had integrated into the genome of infected cells. The integration of HIV into the genome of infected cells allows the virus to persist, and is the major obstacle to curing HIV infection.
Importantly, the study was performed only in cells in a laboratory dish. No tests have been conducted yet in animals, and there is a long way to go before they might be performed in humans.
Contrary to the impression given by some of the media reports, the approach achieved varying degrees of success in the laboratory dish experiments. In the case of HIV-infected T cells, the technique appeared to reduce the proportion containing integrated HIV by about 50 percent. The Philadelphia Enquirer story picked up on this detail, noting: “the scissors did not work on every cell.” When the researchers assessed the effects of equipping cells with the gene-editing tool prior to exposing them to HIV, there was evidence of complete protection against infection by some HIV variants, whereas other HIV variants showed reduced levels but were still able to infect some of the cells.
There are a number of important challenges that need to be addressed in order to make this type of approach suitable for testing in people:
- Safety: The major concern with gene-editing technologies is the potential for “off-target” effects—damage to genes that were not the intended targets. Unwanted damage to human genes could cause serious harm. Although no evidence of off-target effects was uncovered in the laboratory-dish experiments, further research, including animal-model studies, will be necessary to evaluate safety.
- Activity: As noted above, the approach wasn’t always successful at editing out HIV from infected cells, or at protecting uninfected cells. The researchers also point out that the genetic variability of HIV poses a challenge, because the gene-editing technology targets specific HIV genetic sequences that may not be the same in all the viruses circulating globally, or even all the viruses present in an HIV-positive individual.
- Delivery: As highlighted in the story in the Scientist, an overarching challenge with this type of technology is figuring out how to safely deliver it to all the cells in which it would be needed. Latently infected cells containing integrated HIV are extremely rare in HIV-positive people on effective antiretroviral therapy, and so far no marker has been identified that would allow these cells to be specifically targeted by a delivery method. In the absence of such a marker, the daunting task would be to try to deliver the gene-editing technology into every cell in the body that might be susceptible to HIV infection. A related concern is that the gene-editing tool used in this study is a bacterial enzyme (named CRISPR-Cas9) which would be recognized as foreign by the human immune system.
The idea of trying to snip integrated HIV DNA out of the genome of infected cells is not new; among the first to publicly propose it was a company called Cellectis in 2008. Last year, a German research group published a study in HIV-infected humanized mice using a similar idea, but with a different type of “scissor” technology that becomes active only in infected cells in which an HIV protein (Tat) is present (this likely prevents the approach from working in latently infected cells, due to the absence of the HIV Tat protein).
More broadly, there is widespread scientific interest in the potential of gene-editing technologies to correct genetic disorders. The high level of interest has already spurred scientific advances in recent years and there is reason to be optimistic that further improvements in gene-editing technologies can be achieved.
There are ongoing human clinical trials of a gene-editing-based candidate developed by Sangamo BioSciences named SB-728-T that does not target HIV, but instead modifies CD4 T cells with the aim of removing the CCR5 coreceptor (see the “Research Toward a Cure and Immune-Based and Gene Therapies” chapter of TAG’s 2014 Pipeline Report for additional information). The reason why this approach is further advanced is that the gene editing is done in the laboratory. The CD4 T cells are extracted from each trial participant, modified in the laboratory, and then expanded in number and reinfused (avoiding the need to deliver the gene-editing technology into the body).
For a recent, technical scientific review of gene-editing technologies in HIV research, see:
Newer Gene Editing Technologies toward HIV Gene Therapy – N. Manjunath, Guohua Yi, Ying Dang, and Premlata Shankar, Viruses, November 14, 2013