A long-term public-private partnership should be developed to overcome barriers to a cure for HIV infection, a group of leading HIV researchers from academia and industry declare today in the journal Science.
Calling on colleagues, industry and donors to meet the challenge of curing HIV infection, the researchers say that exploring the possibility of engineering a drug-free remission from HIV replication – which probably requires complete elimination of the virus from the body – should be a priority.
"Without a vaccine, we are left with the substantial financial burden of lifelong treatment for tens of millions of people," said Professor Douglas Richman, director of the Center for AIDS Research at the University of California San Diego.
"Success – if achieved – will not occur quickly," Richman added. "But, bear in mind, the dramatic success of combination antiretroviral therapy which has transformed HIV/AIDS in the developed world and is beginning to impact the developing world required 15 years of substantial effort."
A similar call was recently issued by the Treatment Action Group, a US-based advocacy organisation, which recommended to the US National Institute of Allergy and Infectious Diseases that research into an HIV cure should be reinvigorated, with particular attention given to funding innovative investigators, developing animal models in order to learn more about HIV persistence and assays to measure latent virus and the effects of treatment.
"We are not going to find a cure for AIDS until we get serious and put it on the map," said Mark Harrington, executive director of TAG. "A collaboration between independent scientists and the drug industry is a practical proposal to get this research moving," said Harrington, welcoming today’s proposal.
Both groups propose that the goal of HIV therapeutics should be a drug-free remission – the long-term absence of detectable HIV replication without the need for ongoing treatment.
Achieving this goal requires understanding how HIV continues to persist at low levels in the bloodstream, and identifying all the reservoirs from which HIV continues to spring despite highly suppressive therapy, the researchers say.
In his recent plenary lecture at the Sixteenth Conference on Retroviruses and Opportunistic Infections Robert Siliciano presented evidence that currently available drugs are able to eliminate ongoing rounds of HIV replication, suppressing viral load below 1 copy per ml, and that any virus detectable in the bloodstream is likely to be the product of a previously latently infected cell.
However, intensification of therapy with currently available drugs did not seem to eliminate the release of virus from latently infected cells, suggesting, said Siliciano, that current treatment has reached its limit.
Siliciano explained that the cell reservoirs in which HIV persists in a latent form are still not fully understood. In addition the factors that keep HIV latent within those cells, often for many years, are not understood.
Better animal models, as well as human subjects for studies involving numerous intestinal and lymph node biopsies, are needed before the reservoirs are fully characterised and the mechanisms that maintain them understood.
Mechanisms for purging the reservoir need to identified and tested, an enterprise that will require screening of pharmaceutical compound libraries and substantial incentives for the private sector to develop research programmes.
The first major step towards reactivating the latently infected cells in the reservoir, Prof. Richman told aidsmap, is “identifying cellular targets which, if modulated, would activate only latently infected cells, since you can’t activate every cell in the body without killing someone. Step two is validating these targets in animal models and in drug discovery – hence the need for coordination.”
Tests that can accurately quantify very small amounts of HIV in tissues, which can measure latent HIV in one in a million CD4 cells and highly sensitive tests that can identify cells containing latent, integrated HIV provirus will be needed too, in order to measure the success of any therapeutic approaches.
The researchers making the case for a cure include David Margolis of the University of North Carolina at Chapel Hill, Warner Greene of the Gladstone Institute of Virology and Immunology, San Francisco, Daria Hazuda of Merck & Co, and Roger Pomerantz of Tibotec Pharmaceuticals. The longstanding AIDS treatment activist Martin Delaney, who died in January, was also an author of the article.
The call coincides with a huge funding stimulus for AIDS research, that will arrive in the form of a $10 billion uplift to the US National Institutes of Health budget approved as part of President Obama’s stimulus package.
Blogging at AIDSMeds.com, editor Peter Staley noted last week that HIV research could attract up to $1 billion of that allocation over the next two years, with new money likely to be devoted to expanding existing research programmes and funding well-reviewed applications that just missed funding in recent funding rounds.
But whether research into HIV eradication will be able to benefit from this stimulus is less clear. NIH issued a call for information about research priorities in the quest for HIV eradication last year, and is currently digesting responses. But at present the word `cure` does not feature in the NIH Office of AIDS Research list of critical AIDS research priorities for 2010, nor in its 2009 budget.
“It’s no wonder that scientists who apply for funding to study HIV latency are so often turned down: the term does not feature in the NIH plan,” commented Bob Huff of Treatment Action Group in the February edition of the group’s newsletter TAGLine.
However, persistence of HIV reservoirs will be one of a lengthy list of areas that will be given priority for funding under challenge grants being offered with stimulus package funding.
However, challenge grants will only last for two years, with work to be completed by 2011.
“The good news is, new money is coming. The bad news is, it's going away after two years with no guarantee of continuity unless the underlying NIH base budget, currently $30 billion a year, is increased, multi-year, over inflation,” commented Mark Harrington, Executive Director of the Treatment Action Group.
“So, the prospects of a big new cure project at this time are medium to low.”
Prof. Richman told aidsmap that a collaborative project was needed in order to prioritise and coordinate research.
“The funding that is available through the stimulus package is very restricted. It would be useful for investigators who want to look at individual targets but it doesn’t address the wider questions and the need for coordination.”
Richman D et al. The challenge of finding a cure for HIV infection. Science 323 (5919): 1304 - 1307, 2009. DOI: 10.1126/science.1165706