In London in mid-December, Dr. John Frater of Oxford University opened a meeting on HIV cure research with a recap of the most important cure research stories of 2013. He divided them into three categories: those that taught us more about the virus, about the immune system, and about the patients. Below is a brief summary of each.
About the Virus
How to Measure the Reservoir
Dr. Janet Siliciano teamed up with a large group of colleagues to compare different methodologies, or assays, to measure the minute levels of virus that remain after a patient’s infection is well-suppressed by antiretroviral therapy. The study, funded by amfAR’s ARCHE program, compared the assay developed by the Siliciano lab—called the viral outgrowth assay and widely considered to be the gold standard—to ten other assays. Despite the pressing need for a simple, accurate measure of the viral reservoir, none of the assays reviewed fulfilled those criteria.
As noted above, the viral outgrowth assay has long been considered the gold-standard method of measuring reservoir size. In other studies funded by amfAR’s ARCHE program, Dr. Robert Siliciano took a closer look at the assay developed in his lab and discovered that it also does not accurately measure all of the virus remaining in a patient that is capable of replicating. In fact, his team discovered that this assay underestimates the size of the reservoir by an average of 60-fold, but this factor of underestimation differs widely between patients.
Does HIV Continue to Replicate?
A group of Spanish researchers, including amfAR grantee Dr. Maria Buzón, continues to investigate whether the virus that cannot be cleared by antiretroviral therapy—commonly referred to as the reservoir—is truly latent, or whether there may be levels of replication that are so low they are not commonly detected. They provided evidence that there may in fact be ongoing replication, which has implications for how HIV infection should be treated and ultimately cured.
About the Immune System
Using the Immune System to Clear Latently Infected Cells
ARCHE grantee Dr. Una O’Doherty worked with colleagues to determine that, contrary to previous belief: latently infected cells produce low levels of viral proteins; these proteins can be detected by the immune system; and the immune system can use this signaling to kill those latent cells that are producing the viral protein Gag. These findings have the potential to inform the development of therapeutic vaccines that may form part of a cure strategy.
Using a Virus to Counter a Virus
Dr. Louis Picker and colleagues tested a vaccine delivered to monkeys using another virus called cytomegalovirus. Monkeys that received the vaccine and were then infected by SIV, the monkey equivalent of HIV, were able to control virus levels and, in some cases, even cleared the viral infection over time. It remains to be seen whether this vaccine could clear the virus in monkeys—and/or ultimately in humans—who are already infected with the virus.
Can HIV Be Cured With Antibodies?
Dr. Dan Barouch and colleagues infused a cocktail of antibodies into monkeys that were already infected with SIV and noted a dramatic decline in levels of virus, as well as improved function in other aspects of the immune system. While it remains to be determined whether viral infection might be cured this way, the researchers suggested that such a mix of antibodies might form an effective new therapy for HIV infection.
About the Patients
An Infant Cured of HIV
In March, Dr. Deborah Persaud made the stunning announcement that an infant, born HIV positive in Mississippi, had been cured using only antiretroviral therapy delivered at a treatment dose shortly after birth. The researchers who confirmed the cure are members of an ARCHE-funded consortium formed to investigate cases of potential cure in pediatric patients.
Controlling HIV After Treatment is Stopped
Not long after the Mississippi infant case was announced, a group of French researchers published details of 14 HIV-positive people who took antiretroviral therapy for three years, beginning within the first few weeks of infection. These patients stopped therapy for various reasons, and for more than seven years they have not experienced resurgence in their virus levels.
A Systematic Study of Post-Treatment Control
A research team in the United Kingdom conducted a trial to determine what proportion of patients might achieve a state of post-treatment control similar to the French patients (see above). Their study, called SPARTAC, revealed that it is a relatively rare phenomenon. There were intriguing suggestions that the greatest clinical benefit occurred in patients who had the longer course of therapy and, consistent with a growing number of studies, who initiated treatment very soon after infection.
Treatment Early in Infection
TREAT Asia member and ARCHE grantee Dr. Jintanat Ananworanich described an ongoing study in Thailand in which patients initiated antiretroviral therapy an average of only 17 days after HIV infection. The viral reservoirs in several of those patients are at or near undetectable levels. Further studies may reveal whether any of these patients are cured.
Shock and Kill – Vorinostat
ARCHE grantee Dr. Sharon Lewin described results of a study in Melbourne, Australia, of patients who took an anti-cancer drug called vorinostat, which has been shown in the test tube to awaken infected cells out of latency—a step thought critical by some towards curing HIV. There are hints that the drug works, albeit partially, when HIV-infected patients take it.
Shock and Kill – Panobinostat
In another shock and kill study, Danish researchers funded by amfAR tested panobinostat, an investigational anti-cancer drug that belongs to the same drug class as vorinostat, in a group of HIV-infected patients. Preliminary results indicate it may be the most potent drug tested in this class to awaken latently infected cells. More results are expected in the coming year.
The Boston Patients
ARCHE grantee Dr. Timothy Henrich reported the results of two HIV-infected patients whose concurrent cancer had been treated with stem cell transplants. Afterwards, the virus in each patient could not be detected using the most sophisticated laboratory tests available for an unusually long period of time, 12 and 32 weeks, but ultimately each patient experienced a rebound in virus.