Cure Research Media Monitor
Scientific research into curing HIV infection has expanded significantly in recent years, gaining a much higher profile in the press. Unfortunately, media coverage of cure research can be inaccurate and tends to overhype preliminary results. The purpose of this page is to provide TAG’s perspective on cure research in the news, with the aim of placing stories in context and addressing any inaccuracies. A glossary of terms used in HIV cure research is available on the Project Inform website. Links to recent cure research coverage by both the mainstream media and community sources can be found on TAG's cure research resource page.
- Israeli scientists see breakthrough in AIDS cure (November 2016)
- British scientists on brink of HIV cure (October 2016)
- Cure for HIV possible “within three years” (April 2016)
- New Breakthrough May Lead to HIV Relapse Cure (October 2015)
- Claim that Gilead Sciences May Have Found an HIV Cure (May 2015)
- FDA Gives HIV 'Functional Cure' Go-Ahead For Human Trials (March 2015)
- Doctors “Cure” HIV Patient with Cord Blood Transplant (November 2014, updated July 2015)
- French Scientists Find Mechanism for Spontaneous HIV Cure (November 2014)
- Gene Editing Technique Removes HIV from Infected Cells (July 2014)
- Stem Cell Transplants for Cancers “Cleared” HIV in Two Australians (July 2014)
- Israeli scientists see breakthrough in AIDS cure – The Times of Israel, November 1, 2016
- Israeli researchers offer some hope for HIV carriers – Arutz Sheva 7, November 1, 2016
- Israeli research successful in identifying possible HIV, AIDS cure – The Jerusalem Post, November 2, 2016
The media articles describe results of a new study that do not appear to have been published, and it’s not clear if they were presented at a conference. The researchers have not responded to emails asking if the results have been published or presented. A previous study describing the approach is available online in the open access journal AIDS Research & Therapy, which charges authors to publish articles and has unusually rapid peer review (all papers have to be reviewed within two weeks):
Specific eradication of HIV-1 from infected cultured cells - Aviad Levin, Zvi Hayouka, Assaf Friedler and Abraham Loyter, AIDS Research and Therapy, August 19, 2010
TAG's commentary: These stories are based entirely on results obtained in laboratory dish experiments. The researchers have developed peptides (fragments of proteins) that enhance the ability of HIV to integrate its genes into the genome of the cells that it infects. Normally only one or two copies of HIV integrate into a single infected cell, but the peptides are reported to increase this number. In the published study, adding the peptides to cultured HIV-infected cells in a laboratory dish led to an increase in viral replication which was followed, about a week later, by increased death of infected cells due to apoptosis (cellular suicide). The combination of the peptides with a protease inhibitor led to a more rapid onset of the death of HIV-infected cells.
The recent news articles suggest that a similar experiment has now been conducted using cells sampled from HIV-positive individuals instead of the laboratory cell lines employed in the published paper. If the stories are accurate, similar effects were seen, with the approach reducing the number of HIV-infected cells over time in a laboratory dish.
While some of the headlines claim this may be a step toward an HIV cure, this claim is massively premature – it is not yet known if the approach could be used in people, or if there would be a similar effect on the number of HIV-infected cells. Importantly, it’s not clear how the approach would work against the HIV reservoir, which presents the biggest obstacle to curing HIV infection. The HIV reservoir consists of cells containing integrated virus that is latent (inactive) and the peptides appear to work by promoting the integration of viruses that are actively replicating. Thus there is no obvious mechanism by which the combination of the peptides with antiretroviral therapy would affect the latent HIV reservoir in the absence of an additional strategy to try and activate the latent HIV. Furthermore, studies assessing whether the peptides can be safely delivered to any animal, let alone humans, do not appear to have been conducted as yet.
Hopefully the study being reported in these news stories will be published soon, allowing a more thorough assessment of the results.
- British scientists on brink of HIV cure (headline now corrected to "British scientists hopeful for HIV cure") – The Sunday Times, October 2, 2016 (registration required)
- HIV cure close after disease 'vanishes' from blood of British man (now amended to the still inaccurate "HIV cure possible after disease becomes undetectable in blood of British man") - The Daily Telegraph, October 2, 2016
- Why talk of a cure for HIV is premature - Fergus Walsh, BBC News, October 3, 2016 (an accurate story written with the cooperation of the researchers).
Community-based responses and articles:
- Media reports of a British HIV cure 'breakthrough' are premature - Keith Alcorn, AIDSMap, October 3, 2016
- U.K. Papers Erroneously Report, Yet Again, That an HIV Cure Is Near - Ben Ryan, POZ Magazine, October 3, 2016
- No Proof of New HIV Cure, Despite Headlines -- Here's What We Know - Roger Pebody, TheBody.com, October 3, 2016
- Reports Of UK HIV Cure Are Misleading - Miranda Smith, Doherty Institute/NAPWHA HIV Cure Website, October 4, 2016
- 'Infuriating': People With HIV, Doctors, Advocates Speak Out on Bad 'HIV Cure' Reporting - JD Davids, TheBody.com, October 4, 2016
Unknown, the original Times story appears to be based on interviews with researchers and a single study participant.
TAG's commentary: These stories, and particularly the headlines, are highly misleading and inaccurate. The subject matter is an ongoing clinical trial in the UK that is not expected to cure anyone of HIV infection. Known as the RIVER study, it represents an important first exploration of the combined effects of a therapeutic HIV vaccine and an HDAC inhibitor (vorinostat) on the HIV reservoir in individuals who started antiretroviral therapy (ART) very soon after becoming infected.
The stories state that one participant has undetectable HIV viral load in their blood but this is normal for individuals on antiretroviral therapy. No measurements of the HIV reservoir have yet been performed. The journalist appears to have interviewed the study participant and misunderstood the significance of undetectable viral load, a misunderstanding that has now beem amplified in secondary media reporting.
The current best approach for assessing whether HIV is still present is to interrupt ART, and the researcher Sarah Fidler makes it clear in the articles that this is not yet being considered. As some of the more accurate media coverage explains, even if HIV remains undetectable after an ART interruption long-term follow up is required because there have been several cases where viral load remained undetectable for months or--in the case of the Mississippi baby--years before rebounding.
A recent study that combined a therapeutic HIV vaccine with an HDAC inhibitor revealed some evidence of a slight decline the HIV reservoir, but there was no effect on viral load rebound when ART was interrupted. Participants in this study had not recently acquired HIV.
The bottom line is that it appears extremely unlikely that anyone participating in the RIVER trial will be cured, but the information learned is expected to make a contribution to the ongoing effort to develop a cure. Results are expected in 2018.
As has happened in the past, an effort is now underway to secure corrections to the Times and Telegraph articles.
The Daily Telegraph article and examples of the media coverage that followed it:
- Cure for HIV possible within three years as scientists snip virus from cells – The Daily Telegraph, April 1, 2016. Update April 6, 2016: After receiving complaints, The Daily Telegraph has creditably responded by editing the headline and first paragraph to remove the claim that the approach may cure HIV infection "within three years" or "a few years."
- HIV Could Be Cured Within Three Years - Fortune, April 1, 2016
- Cure for HIV reportedly 3 years away - FoxNews.com, April 2, 2016
Examples of initial media coverage:
- Scientists remove HIV-1 from genome of human immune cells – United Press International, March 21, 2016
- Temple researchers snip HIV from infected cells, suggesting a cure is possible - Philly.com, March 23, 2016
Community-based responses and articles:
- Media Outlets Falsely Claim That a Cure for HIV May Be Only Three Years Away - Benjamin Ryan, POZ Magazine, April 4, 2016
- Snipping the HIV Genome Out of Latently Infected Cells – TAG’s Michael Palm HIV Basic Science, Vaccines, and Cure Project Blog, March 23, 2016
- Gene therapy snips HIV out of infected cells and makes uninfected cells resistant - Gus Cairns, AIDSMap, March 30. 2016
- Scientific journal article: Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing - Scientific Reports, March 4, 2016
- Temple University Press Release: Scientists at Lewis Katz School of Medicine at Temple University Eliminate HIV-1 from Genome of Human T-Cells - March 21, 2016
- Excision BioTherapeutics Inc. Press Release: Use of CRISPR Cas9 Gene Editing Therapeutic Shown to Permanently Inactivate HIV-1 in Patient's Blood for First Time - March 21, 2016
TAG's commentary: The story is about a gene-editing approach designed to try and eliminate HIV from infected cells that was already covered on this page two years ago (the challenges involved in trying to translate the approach into a therapy remain the same as described then).
The approach is still only being tested in laboratory experiments and it is not yet known if it can be translated into a therapy suitable for administering to people.
The renewed media attention was caused by the publication of a scientific paper in the journal Scientific Reports (see TAG’s blog post for details), which was promoted by press releases from the research institution, Temple University, and Excision BioTherapeutics, a company the lead researcher Kamel Khalili has founded to try and commercialize the approach (in partnership with Temple).
The scientific paper was published online on March 4, followed by the press releases on March 21, and received an initial round of media coverage that was reasonably accurate, although somewhat over-optimistic about the immediate prospects for the approach.
Then, on April 1, The Daily Telegraph published an article claiming that it might be possible to find out whether the approach can cure HIV infection within three years - this is outrageously false.
Even under the most optimistic scenarios, it is likely to be more than three years before even the first clinical trials are possible (and it is not known yet if human trials will be possible).
In an excellent article for POZ Magazine, Ben Ryan obtained a quote from Kamel Khalili in response to The Daily Telegraph's coverage: “We have made no claim that our technology will cure HIV in three years.”
Unfortunately, as often happens with attention-grabbing headlines, many other media outlets around the world are now parroting The Daily Telegraph’s false claim that this research may lead to an HIV cure “within three years.”
Sarah Knapton, The Daily Telegraph's Science Editor and author of the article, has so far refused requests to make appropriate corrections.
Unfortunately this is the second example of irresponsible, misleading coverage of HIV cure research by The Daily Telegraph. Such articles exploit people’s hopes for an HIV cure in order to generate web traffic and social media attention, a tactic that is reprehensible and unethical. In that prior case, however, The Daily Telegraph did at least eventually correct the errors when they were brought to their attention (see this POZ Magazine article by Ben Ryan and the updates at the end of this blog post). Hopefully this latest erroneous article will eventually be corrected as well.
Update April 6, 2016: As noted above, The Daily Telegraph has thankfullly now responded by editing the headline and first paragraph to remove the mistaken claim that the approach may cure HIV infection "within three years" or "a few years."
- New Breakthrough May Lead to HIV Relapse Cure - Indo-Asian News Service, October 11, 2015
- HIV breakthrough could lead to a CURE: Scientists identify markers on immune cells that 'predict who can stop drug therapy and stay well' – Daily Mail, October 9, 2015
- Doctors report major breakthrough in understanding virus that causes AIDS – New York Daily News, October 9, 2015
- Scientific journal article: Immunological biomarkers predict HIV-1 viral rebound after treatment interruption - Nature Communications, October 9, 2015
- Press release: HIV discovery – biomarkers predict virus return when treatment is stopped – University of New South Wales, October 9, 2015
Examples of media coverage:
- Gilead Sciences (GILD) May Have Found A Cure For HIV! – CNA Finance, May 18, 2015
- This Experimental Drug Could Finally Cure HIV - Motley Fool, May 18, 2015
Unknown, possibly a Gilead Sciences presentation to investors, although it is highly unlikely the company claimed that the drug may cure HIV.
TAG's commentary: For reasons that are unclear, two websites that cover financial news have published wildly erroneous stories suggesting the company Gilead Sciences may have discovered a cure for HIV.
The drug in question is named GS-9620, and it has shown some promise in a small study involving monkeys infected with SIV (HIV’s simian equivalent). Administration of GS-9620 to macaques on antiretroviral therapy (ART) appeared to slightly reduce levels of the latent SIV reservoir, but it did not lead to a cure. When ART was interrupted, viral load rebounded in all animals, and there was no evidence that the viral load rebound was slower or delayed in macaques that received GS-9620. However, when viral load stabilized (described as the viral load “set point”), levels were somewhat lower in GS-9620 recipients.
These data were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) earlier this year, and a webcast of the presentation is available online. Many news outlets and community-based organizations (including TAG) covered the presentation at the time (e.g. see articles from AIDSMap and Project Inform).
Evidence suggests GS-9620 may have a dual mechanism of action, both inducing production of virus by latently infected CD4 T cells and enhancing immune responses (such as natural killer cells), that could potentially contribute to clearing the infected CD4 T cells. GS-9620 interacts with toll-like receptor 7, an immune cell receptor involved in the recognition of pathogens, and has been studied in people with hepatitis B and reported to be safe.
An initial phase I trial in HIV-positive individuals is now underway and results should help shed light on whether GS-9620 might be able to reduce the latent HIV reservoir and potentially contribute to achieving a cure. But yesterday’s headlines suggesting that GS-9620 might be a cure for HIV are completely incorrect and irresponsible.
Examples of media coverage:
- FDA Gives HIV 'Functional Cure' Go-Ahead For Human Trials: Functional HIV Cure Step Closer To Reality With FDA Approval Of Clinical Human Trials – Medical Daily, March 10, 2015
- Study of potential HIV 'cure' wins FDA nod - San Francisco Business Times, March 3, 2015
- Press Release: CIRM-funded Clinical Trial Aimed at Blocking HIV/AIDS in People Gets the Go Ahead - California Institute for Regenerative Medicine, March 3, 2015
TAG's commentary: These stories, which have been widely shared on social media (particularly the Medical Daily article), were prompted by a news release issued by the California Institute for Regenerative Medicine (CIRM). CIRM is supporting a team at the City of Hope in Los Angeles that plans to genetically modify stem cells to render them resistant to HIV, and test whether administration of these stem cells to HIV-positive individuals has a therapeutic effect.
The press release announced that the US Food and Drug Administration (FDA) has given approval for the conduct of a clinical trial in HIV-positive individuals experiencing a poor response to antiretroviral therapy (ART).
The trial will extract stem cells from the study participants, modify them with an approach developed by Sangamo BioSciences that aims to prevent expression of the CCR5 co-receptor that most HIV strains use to infect cells, then reinfuse the stem cells in hopes that they generate HIV-resistant immune cells (particularly CD4 T cells, HIV’s main target). Stem cells are responsible for generating all the different types of immune cells in the body, including CD4 T cells.
Sangamo’s approach has been used in several other clinical trials to modify CD4 T cells that are extracted from study participants and reinfused. The results have shown overall increases in CD4 T cells numbers, and a few participants have shown evidence of some degree of HIV viral load control after an ART interruption, but there have been no cases of a “functional cure” of HIV infection. The term “functional cure” is generally used to refer to a state in which HIV is not eradicated, but completely controlled without ongoing treatment, in a way that prevents the virus from causing any illness.
The problem with the Medical Daily and San Francisco Business Times headlines is that there is no evidence that the plan to deliver gene-modified stem cells will lead to a “cure” or a “functional cure” of HIV. The whole purpose of clinical trials is to assess the effects of an intervention, whereas the headlines mistakenly pre-judge what the effect of the intervention will be.
Previous trials involving transplantation of stem cells that were gene-modified to be resistant to HIV have found that the numbers of HIV-resistant CD4 T cells generated were very low. The new CIRM trial is an encouraging first step toward assessing whether stem cells modified with the Sangamo approach will perform better, but it is unfortunately extremely premature and misleading to describe the approach as a “functional cure” or potential “cure.”
Examples of media coverage:
- Primer Paciente "Curado" del VIH por un Trasplante de Sangre de Cordón Umbilical – El Mundo, November 6, 2014
- Doctors "Cure" HIV Patient with Blood Transplant – Local: Spain’s News in English, November 6, 2014
- HIV Cure News 2014: Barcelona Doctors Believe They've Found Cure to AIDS-Causing Virus – Latin Post, November 8, 2014
- Spain to Research HIV Cure Using Umbilical Cord Blood – El País, November 10, 2014
- HIV Breakthrough! Spain Finds Functional Cure For HIV Virus (Confirmed) - In South Africa Today, July 13, 2015
- Press release: La ONT y la SEHH Apuestan por el Trasplante de Sangre de Cordón Umbilical para Erradicar el VIH en Pacientes con Cáncer Hematológico – Ministerio de Sanidad, Servicios Sociales e Igualdad, La Organización Nacional de Trasplantes y la Sociedad Española de Hematología y Hemoterapia, November 6, 2014
- Presentation by Rafael F. Duarte at a symposium titled Trasplante de Progenitores Hematopoyéticos Alogénico y Curación de VIH – LVI Congreso Nacional de la Sociedad Española de Hematología y Hemoterapia, November 7, 2014
- Abstract by Rafael F. Duarte, et al. (Embargoed until December 10, 2014): Allogeneic Transplantation with CCR5Δ32/Δ32 Cord Blood Hematopoietic Cells in a HIV-Infected Patient– 56th American Society of Hematology Annual Meeting and Exposition, San Francisco, CA, December 6–9, 2014
TAG's commentary: The initial trigger for this story, which first appeared in the Spanish newspaper El Mundo, was a press release issued on November 6 by the National Transplant Organization, the Spanish Hematology and Hemotherapy Society, and the Ministry of Health. The primary focus of the release was the launch of a new research project that aims to provide cord blood stem cells from donors heterozygous for the CCR5Δ32 mutation to HIV-positive people who require stem cell transplants to treat cancers. The hope is that this approach can both treat the cancer and recapitulate the cure of HIV achieved in Timothy Brown (the only individual considered cured of HIV infection to date). But the release also mentions that the approach “succeeded in an HIV patient with lymphoma treated in 2013.” It is the reference to this previously unknown case that has become the focus of news reporting, and unfortunately misinformation has seeped into some of the articles.
The individual, who was treated in Barcelona, survived for only three months after the transplantation procedure due to a recurrence of the lymphoma (a Latin Post article misreports the posttransplant survival as three years). According to one of the researchers involved, HIV became undetectable in blood samples (by multiple tests), but antiretroviral therapy was not stopped and it was never proved that the individual was cured. The El Mundo article states that tissues and cerebrospinal fluid were also analyzed, but this appears to be an error. The potentially encouraging finding for the future is that the cord blood stem cell transplant with the CCR5Δ32 mutation did eventually engraft, although it required an additional cord blood stem cell transplant from a normal donor to assist the process. As with Timothy Brown, the individual was found to have developed an immune system resistant to CCR5-tropic HIV strains as a result of the engraftment of the transplant. The researchers note that a potential advantage of cord blood stem cells is that less stringent genetic matching of donor and recipient is required compared with adult stem cells (Brown’s procedure involved the latter).
A manuscript about the case has been submitted for publication, so more details will be forthcoming (May 2015 update: the case report is now published in The Lancet HIV). The lead researcher, Rafael Duarte, is due to present at the upcoming 56th American Society of Hematology Annual Meeting and Exposition, and his abstract is available online; however, it is under embargo until after the conference ends.
The media stories that have followed the initial El Mundo report offer examples of how misleading hype can be generated. The Latin Post article is headlined is “Barcelona Doctors Believe They've Found Cure to AIDS-Causing Virus,” and it opens with this stark sentence: “Spanish doctors in Barcelona believe they've found the cure to HIV.” The fact that the procedure itself is associated with a 15–25 percent risk of mortality is never mentioned, and its limitation to people with life-threatening cancers is referenced only in the last paragraph of the piece. Even then it states that the procedure is “primarily designed to assist HIV patients suffering from cancer,” when the reality is that it can only be tried in individuals requiring stem cell transplants for cancers. A subsequent piece in El País does far better and contains a clear and accurate description of the research project, although it also contains a quote from Duarte that HIV was “eliminated” from the individual in Barcelona and the evidence does not appear sufficient to support this claim.
Update July 27, 2015: Strangely, the inaccurate and misleading Latino Post story has suddenly reappeared in mid-2015 on Africa-based news sites, in a slightly altered form with an even more horrendously false headline: "HIV Breakthrough! Spain Finds Functional Cure For HIV Virus (Confirmed)." As far as I can tell this version first appeared on the site News 24 Zimbabwe on June 24, but has more recently been added to In South Africa Today. Unfortunately, these inaccurate articles are now being widely circulated on social media.
As mentioned in a prior posting, there are two research projects ongoing in the U.S. that are seeking to identify donors homozygous for the CCR5Δ32 mutation for HIV-positive people requiring stem cell transplants for cancers. One is for individuals 15 years or older and involves adult stem cells; the other is for both children and adults and will employ cord blood stem cells.
- Allogeneic Transplant in HIV Patients (BMT CTN 0903)
- IMPAACT P1107: Effects of Cord Blood Transplantation with CCR5Δ32 Donor Cells on HIV Persistence
The company StemCyte has for some time been developing a bank of cord blood stem cells from donors homozygous for the CCR5Δ32 mutation and can make them available in individual cases (it supplied the cells for the man in Barcelona). Last year it provided cells for an HIV-positive boy with cancer in Minnesota, but he died due to graft-versus-host disease shortly after the transplant.
Lawrence Petz, the Medical Director of StemCyte, describes the company’s work in a recently published open-access review:
Cure of HIV-Infected Leukemia Patients with Cord Blood Transplantation – J Leuk 2014, 2:3
Examples of media coverage:
- French Scientists Find Mechanism for Spontaneous HIV Cure – Agence France-Presse, November 4, 2014
- Scientists See Mechanism for Spontaneous HIV “Cure” (Update) – Agence France-Presse, November 4, 2014
- HIV: Genetic Mutation Leads to Two Men Being “Spontaneously Cured” of Virus – International Business Times, November 4, 2014
- So-Called HIV ‘Cure’ Is Not Actually a Cure – Newsweek, November 5, 2014
- Scientific journal article: HIV Infection en Route to Endogenization: Two Cases – Clinical Microbiology and Infection, November 4, 2014
TAG's commentary: Agence France-Presse launched this story onto the Internet on November 4, and it is being reposted and picked up by an increasing number of other outlets. The story relates to a scientific paper published on the same day in a little-known journal called Clinical Microbiology and Infection. The paper, authored by a group of French scientists (one of whom, Didier Raoult, is also the editor of the journal), describes two individuals who are reported to be HIV-positive but show no detectable HIV genetic material (RNA and DNA) in their blood by "standard methods." However, the lower limit of detection for the tests used is not stated. The individuals were identified from a cohort of elite controllers, who frequently have HIV RNA levels below the limit of detection of standard viral load tests (less than 400 copies or less than 50 copies depending on the test). No testing using more recently developed ultrasensitive HIV RNA assays is reported. One of the individuals was diagnosed HIV-positive in 1985; the other was diagnosed in 2011 and is thought to have been infected for a shorter period of around 3–6 years. The researchers used "deep sequencing" techniques to find and analyze HIV DNA in blood samples from the two cases, and report that the viral DNA they found showed a significant number of mutations, which they conclude have inactivated the virus. Based on this preliminary finding, derived only from analysis of peripheral blood and not the lymphoid tissues, where the majority of HIV is known to reside, the researchers claim that both individuals are cured. In one case, CD4 T-cell and CD8 T-cell count data are presented and are normal, whereas in the other no information on these measurements is provided.
From TAG's perspective, the data are not sufficient to justify the claim that these two cases represent cures of HIV infection and not examples of elite control. The hypermutation of HIV in elite controllers has been reported previously, although it is not a universal finding.
The authors of the paper propose an improbable-sounding theory to account for their claims, which is that HIV has become endogenous in some people, which would mean that HIV had managed to integrate into either a sperm or egg cell and then transferred to the offspring of the person in whom this integration took place. Currently, there is absolutely no evidence that this has ever happened with HIV. There are remnants of other ancient retroviruses in the human genome that have undergone this process sometime in the distant past (these are referred to as endogenous retroviruses), but no one has presented evidence that HIV has become endogenous in anybody (it would cause HIV genes to be present in every DNA-containing cell in the body). The authors also propose that the mutations they found in the HIV sequences identified in these two individuals were caused by a human enzyme, APOBEC 3G; this seems less unreasonable because the mutation-inducing activity of APOBEC 3G has been described by many scientists, and, as mentioned above, hypermutation of HIV has been reported in some elite controllers.
In sum, it is possible that something of value for HIV cure research may be learned from these cases, but a lot more information is needed. In the absence of additional information, the statement in some of the headlines that these scientists have found a mechanism for a spontaneous HIV cure is erroneous. To its great credit, Agence France-Presse has produced an update to its original story, which includes several skeptical quotes about the paper from independent scientists. Also, on November 5th, Newsweek published an article disputing the claims made in the paper, noting that the evidence presented is consistent with the two individuals being elite controllers (not cases of HIV cures).
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
TAG's commentary: 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
Examples of media coverage:
- HIV “Cleared” in Two Australian Men after Bone-Marrow Transplants – Sydney Morning Herald, July 19, 2014
- HIV Said Cleared in Two Bone Marrow Transplant Patients – Bloomberg News, July 18, 2014
- Cancer Treatment Clears Two Australian Patients of HIV – Nature News, July 18, 2014
- Presentation at the International AIDS Society Towards an HIV Cure Symposium, Melbourne, Australia, July 19, 2014 (see abstract #PE48LB on page 74 of the symposium abstract book)
- Two Sydney Men Clear HIV after Bone Marrow Transplants – University of New South Wales press release, July 18, 2014
TAG's commentary: The headlines relating to this story are very misleading. There is no evidence as yet that HIV has been “cleared” from these two individuals, as both remain on ART. Rather, HIV is undetectable by a variety of tests. Most of the stories do mention this critical fact, even though the headlines are inaccurate. A news item in the scientific journal Nature, which might be expected to be more accurate than other media, erroneously describes the men as "apparently HIV-free." An article in the New Scientist also specifically addresses concerns about the misleading coverage:
Latest HIV “Cure” Claims Prompt Calls for More Caution – Andy Coghlan and Jessica Hamzelou, New Scientist, July 22, 2014
As this and several other articles point out, recent experience strongly cautions against assuming that the inability to detect HIV means that the virus is no longer present in the body. A previously published report regarding two HIV-positive individuals in Boston who received stem cell transplants to treat cancers described an absence of detectable HIV. These cases received a lot of publicity in July of last year because HIV remained undetectable after ART was interrupted. However, in December, it was announced that viral load had rebounded in both individuals, after 12 weeks in one case and 32 weeks in the other. These results were published on July 22 in the journal Annals of Internal Medicine.
Stem cell transplantation is a high-risk procedure used to treat certain serious cancers. There is significant interest in studying people with HIV who undergo stem cell transplants to treat cancers because of evidence that the procedure contributed to eliminating HIV in Timothy Brown, the only person considered cured of HIV infection. However, Brown received stem cells from a donor with a genetic mutation known as CCR5Δ32, which renders cells resistant to most HIV strains. The Boston patients did not receive stem cells from donors with this mutation.
Of the two Australian cases, one received stem cells from a donor heterozygous for the CCR5Δ32 mutation (they inherited the mutation from one parent, not both), meaning their cells are less susceptible to HIV, but not resistant. The other received stem cells from a normal donor. Conducting an ART interruption is the only way for researchers to assess whether these individuals will maintain undetectable levels of HIV in the absence of ongoing treatment.
A number of research studies are looking into the effects of stem cell transplantation in HIV-positive people who require the procedure as part of treatment for cancer. Two trials in the United States are attempting to find compatible stem cell donors homozygous for the CCR5Δ32 mutation in order to try to repeat the cure achieved in Timothy Brown.
- Allogeneic Transplant in HIV Patients (BMT CTN 0903)
- IMPAACT P1107: Effects of Cord Blood Transplantation with CCR5Δ32 Donor Cells on HIV Persistence
In Europe, the European HIV Cure and Transplant Consortium (EHCTC) is also aiming to try to identify stem cell donors homozygous for the CCR5Δ32 mutation for HIV-positive people requiring stem cell transplants to treat cancers.