A scientific strategy—consisting of seven major research priorities—has been launched by an International AIDS Society working group, according to a report released July 19 and discussed in detail in a two-day symposium taking place July 21 and 22 ahead of the XIX International AIDS Conference (AIDS 2012) in Washington, DC.
The strategy, dubbed “Towards an HIV Cure,” explains Françoise Barré-Sinoussi, PhD, in an accompanying news announcement, “is the result of a collaborative effort which has produced a roadmap that will constructively move HIV cure research forward.” Barré-Sinoussi, the co-discoverer of HIV and researcher at the Institut Pasteur, is co-chair of the group—along with Steven Deeks, MD, of the University of California, San Francisco—consisting of 34 leading HIV scientists and clinicians.
The renewed optimism in the search for an HIV cure among scientists is based on a number of scientific advances that are helping to shed light on why it is that HIV remains persistent.
“What we haven’t had until very recently is clear insights into why HIV persists during therapy,” said Deeks, who is among several scientists at the pre-AIDS 2012 symposium outlining the advances that have been made and the key research that still needs to be conducted. “Our basic understanding of the mechanisms of HIV persistence in latent reservoirs”—the cells and tissues where HIV hides and persists—“is far superior than it was a decade ago. We are entering a stage in the epidemic in which we can seriously begin testing drugs that either prevent latency or which force the virus out of its hiding place, make it susceptible to our current drugs.”
Several recent observations make Barré-Sinoussi, Deeks and many of their colleagues enthusiastic about pursuing cure research.
The case of Timothy Brown, the so-called “Berlin Patient”, who received a stem-cell bone-marrow transplant in 2007 and is now considered to be cured of HIV, has proven that a cure is at least possible. This stem cell transplant worked because the donor was among the one percent of Northern Europeans who lack CCR5, the “doorway” through which HIV enters cells. While it is unrealistic to pursue this risky and costly therapeutic approach for most people, it has nevertheless got scientists thinking about the use of gene therapy to modify a patient’s own immune cells to make them resistant to HIV infection.
The molecular biology regarding how HIV’s DNA becomes integrated in the chromosomes of human cells is the focus of intense research. This work has already led to a number of possible interventions, some of which are being tested in clinical trials.
Recently, in a small study involving people living with HIV, David Margolis, MD, of the University of North Carolina and his colleagues showed that a dose of a drug that inhibits an enzyme involved in HIV silencing leads to rapid production of HIV RNA in the patient’s latently infected cells. This could make such previously unreachable viral reservoirs susceptible to curative strategies. For example, in combination with treatments that enhance host immune defense—therapeutic vaccines are an example—unmasking latent virus might allow clearance of infection.
There is also tremendous interest in “elite controllers”—people living with HIV who maintain undetectable viral loads and high CD4 cell counts without requiring antiretroviral therapy—and the factors that set them apart from those with progressive HIV disease.
There also exists a unique group of patients in France—dubbed the Visconti cohort—who became HIV infected, started antiretroviral therapy early, and were able to successfully stop therapy without rebounds in their viral loads.
A number of strategies to emulate these encouraging findings are being investigated (see below). These include gene therapies, treatment optimization and intensification to eliminate all replication, reversal of HIV latency to increase virus production and block HIV DNA integration, and therapeutic vaccines to enhance the immune system’s ability to control HIV.
These strategies are in line with the seven key priority research areas outlined in the Towards an HIV Cure report and reviewed at the symposium in DC:
- Determine the cellular and viral mechanisms that maintain HIV persistence.
- Determine the tissue and cellular sources of persistent HIV in long-term antiretroviral-treated individuals.
- Determine the origins of immune activation and inflammation in the presence of antiretroviral therapy and their consequences for HIV persistence.
- Determine the host and immune mechanisms that control infection but allow viral persistence.
- Study, compare and validate assays to measure persistent infection.
- Develop and test therapeutic agents or immunological strategies to safely eliminate latent infection in individuals on antiretroviral therapy.
- Develop and test strategies to enhance the capacity of the host response to control active viral replication.
Barré-Sinoussi, Deeks and their colleagues note that substantial resources will be required to address these priorities. Though various government, non-government and private groups have increased their commitment to cure research, the investments are not sufficient. In turn, the IAS group has identified six key steps that need to be taken to enhance the resources available to researchers:
- The establishment of large, multinational collaborations involving experts from multiple disciplines—including those outside of the HIV arena—will likely be needed.
- Translational research involving teams of basic and clinical scientists working side-by-side with knowledge flowing in both directions are needed.
- The optimization of relevant animal models for discovering and testing novel interventions is needed.
- Young researchers need to be mentored and supported, as they are likely to be the source of innovative, out-of-the-box thinking.
- The profound regulatory issues that surround the testing of novel drugs—many with high potential for toxicities—in people living with HIV who are generally doing well will need to be addressed, and a regulatory pathway for advancing candidate therapies through the clinical trial process identified.
- Strong community support is needed to advocate against complacency and to ensure that patients and their communities are fully engaged and informed about the risks and benefits of curative studies.
Ongoing, Recruting and Pending Clinical Trials
A number of clinical trials are planned, or currently underway, to study the safe elimination of latent infection in people living with HIV receiving antiretroviral therapy. These include: