January 29, 2013
On January 16, a scientist named David Harrich and his institution, the Queensland Institute for Medical Research (QIMR) in Brisbane, Australia, issued a press release invoking the word cure in an effort to publicize a scientific paper containing in vitro (lab dish) study results of uncertain significance at best. The release spawned a maelstrom of misleading media coverage that has continued to swirl for weeks afterward.
Several factors seem to have contributed to the story's gaining traction. Harrich's work involves a modified version of an HIV protein (Tat) that can inhibit HIV replication; this was presented as a strategy that "turns HIV on itself." Although this sounds potentially exciting and new (and clearly was appealing to the media), Harrich's paper explains that, going as far back as the late 1980s, several other HIV proteins have been altered in ways that inhibit viral replication. This type of inhibition involves a well-described phenomenon wherein a modified protein (described as a dominant negative protein) can inhibit the function of the unmodified counterpart. The novel claim Harrich makes for his modified Tat protein, named Nullbasic, is that it appears to be able to inhibit several different steps in the HIV life cycle. This claim has yet to be independently verified but, more importantly, inhibiting HIV replication is not the major challenge in attempting to achieve a cure: as Harrich's paper also notes, there is an array of proteins than can inhibit HIV. Furthermore, there are proteins that can completely block HIV from entering target cells (a strategy with many advantages compared to those like Harrich's which attempt to block replication after the virus has entered a cell). The major problem in cure research is delivering these inhibitors to the cells where they are needed, and Harrich's study does not help address this issue at all.
In addition to the notion of turning HIV on itself, news stories glommed onto several egregiously irresponsible and unjustified quotes in the press release:
If this research continues down its strong path, and bear in mind there are many hurdles to clear, we're looking at a cure for AIDS.
The use of the word if and the attempted caveat in the middle of this sentence do not compensate for the wild-eyed claim at the end. Like any other human disease, AIDS cannot be cured in a laboratory dish, and it is impossible to know if you are looking at a cure based on in vitro results.
You would still be infected with HIV, it's not a cure for the virus. But the virus would stay latent, it wouldn't wake up, so it wouldn't develop into AIDS. With a treatment like this, you would maintain a healthy immune system.
Perhaps unintentionally, this quote sounds like an early misunderstanding of HIV pathogenesis that was debunked by the early 1990s. In the original erroneous model, HIV was thought to be latent during the asymptomatic phase of the infection before somehow awakening to cause AIDS. It was subsequently shown that HIV replicates throughout the course of infection, causing a persistent activation of the immune system that leads to a gradual attrition of immune-system resources, ultimately resulting in AIDS. Many media outlets failed to notice this misstatement, and instead just repeated the claim that Harrich's protein could prevent the development of AIDS. Harrich's in vitro results do not even show that Nullbasic causes HIV to "stay latent" in infected cells; rather they report a roughly eight- to tenfold reduction in viral replication.
In case this all sounds like pessimistic naysaying, the good news is that there are several gene therapy approaches that are already in human trials, including approaches that aim to completely protect vulnerable cells from HIV infection (drawing inspiration from the one well-documented case of an individual cured of HIV infection, which involved the transplant of cells lacking the key HIV coreceptor CCR5). These trials are attempting to address the thorny problem of delivering various HIV inhibitors to the most vulnerable cells, and thus are many miles further down the road than Harrich's research (see TAG's cure research resource page for more information).
Additionally, the hype generated by the QIMR press release does not necessarily mean that Harrich's development of Nullbasic is of no value; the apparent ability of the protein to block three different steps of the HIV life cycle has the potential to shed new light on how the Tat protein contributes to various aspects of viral replication, which in turn could reveal novel targets for inhibitors. Harrich's paper is considerably more judicious than the press release in highlighting these prospects, concluding that "the unusual properties conveyed by Nullbasic make it a candidate antiviral agent. At the very least analysis of its mechanism of HIV-1 inhibition could advance discovery of novel antiviral strategies." In addition to the publication in Human Gene Therapy (which has been made freely accessible by the journal), there appear to be just two prior papers describing Nullbasic, both in the open-access journal PLoS One (one in 2009 and the other in 2012).
To try and draw some lessons for interpreting media coverage of scientific publications, it is notable that many of the initial news stories only featured quotes from the QIMR press release and included no comments about the study from independent scientists -- this is one red flag to look out for. Eventually, outlets did begin to quote other sources, such as Frank Wegmann of Oxford University who raised the critical point that an HIV inhibitor is of no value unless it can be delivered to vulnerable cells. Several subsequent stories also highlighted the lack of animal studies and that, even in the most optimistic scenario, human trials are many years away. Perhaps the most disturbing aspect of this particular debacle is that the irresponsible claims of Harrich and QIMR were hugely successful in generating publicity; we must hope that this success does not tempt other scientists to indulge in misleading "cure" hype in the hopes of attracting research funding.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.