In 2016, hopes ran high that an HIV cure may be just around the corner. An experimental approach known as “shock and kill” seemed promising. That treatment takes aim at dormant, undetected traces of the virus lingering within immune cells.
In recent months, however, those hopes have dampened.
While shock and kill can effectively flush HIV from its hiding places in tissue reservoirs, some virus particles may still remain, new research shows. Now researchers are investigating why, in the hopes that the answer will point, if not to a cure, than at least to therapies that will ensure the long-term health of patients.
In March, scientists from the lab of veteran HIV-hunter Dr. Robert Siliciano published research showing that dormant T cells harboring HIV particles will spread through cell division. The discovery was a surprise, because researchers long assumed such cells were inactive. By using a new DNA mapping technique, the Siliciano team found identical HIV fragments, called proviruses, in daughter T-cells.
“We knew before that the [HIV]reservoir is very long-lived,” said Siliciano in a press release. “Now it is clear that these cells aren't just sitting there but are dividing and replenishing themselves."
The standard tests that measure HIV replication, called viral load tests, aren’t sensitive enough to detect such stealth viral spread. Siliciano cautioned that even though the HIV pool may be tiny — a dormant virus particle here or there — it could, at least theoretically, retrigger an active HIV infection.
This sobering news has caused leading scientists to reconsider the challenge of eradicating every last trace of HIV in the body, the definition of a full cure. That task now seems much more daunting.
In a recent review of research on an AIDS cure, Dr. Anthony Fauci, head of the National Institutes of Allergy and Infectious Diseases, was characteristically blunt in assessing the challenges ahead. At this year's International AIDS Conference, held this July in Paris, he told an audience that a cure, though still a worthy goal, was “difficult to impossible.”
While antiretroviral, or ART, medication has significantly prolonged the lives of those infected with HIV, the treatment is still out of reach to many globally. In addition, the drugs have side effects, and long-term health impacts for those in treatment are still unclear. A cure would also eliminate any fear of passing on the virus or seeing HIV bounce back.
The new developments do not mean that shock and kill is dead. However, the strategy may need to be combined with different approaches and weapons to eradicate the silent HIV pool. Already, new therapies, called "lock and block," are being tried to prevent any viral escape from the reservoir to reduce risk of reinfection.
New Target in Sight: Long-Term Remission Without Drugs
In the meantime, Fauci was more excited by promising studies pointing to long-term remission without drugs as a viable treatment plan. A growing body of data shows that some people who initially take ART drugs and later go off them can remain healthy for months and even years. When these patients are tested for HIV infection, their viral load -- a measure of active infection -- is below detectable levels. This has led to the rise of new buzzwords in AIDS circles: “ART-free remission.”
"We are starting to see that control in an ART-free system is attainable,” said Fauci. “I think that’s a more realistic goal to pursue, one that can benefit millions of people now living with this disease. For now, a cure is still proving elusive.”
At this year’s International AIDS Conference, most media coverage focused on cases in which antiretroviral treatment has been interrupted with good results. One attention-grabbing study featured a South African child who appeared HIV-free eight-and-a-half years after stopping medication.
Such long-term remission is not unheard of. Earlier studies have reported on a French teenager whose HIV viral load levels remain undetectable after 11 years. Other work has followed a subset of patients whose infection levels are similarly undetectable after more than four years. These cases were observed in studies; it's unknown how much they reflect what's happening in terms of larger populations. Shock and kill studies have found a wide range of viral rebound times in patients who go off ART.
In his AIDS conference roundup of cure research, Fauci noted that in studies where patients discontinue treatment, the average time for HIV to rebound has already more than doubled. Up until 2000, the virus reappeared within 7 to 14 days of a patient going off medication. Since that time through 2015, the average was 28 days. That’s due in part to better drugs, Fauci said. The increases may also be driven by patients receiving treatment soon after exposure to HIV, which may help maintain stronger immune systems.
“Every lab has a few patients who have a great deal of variability to time they rebound,” Fauci said. "It may be two weeks in some people, or three months, or many months. What we are seeing is, tucked away in there, that people treated with good drugs could stop therapy and go for an extended time” without HIV coming back.
To Fauci, this pattern of increasing remission times, as we move through the third decade of AIDS, is an important finding. It may not be as sexy or definitive as attaining a cure, but remission without drugs would represent a welcome sea change for the 36.7 million people living with HIV, including the 18 million on daily ART pills.
Fauci's also excited about a monkey antibody, alpha4beta7, which has a close human equivalent: the FDA-approved drug vedolizumab that is used to treat Crohn's disease and ulcerative colitis. Fauci's team saw "sustained remission" in macaques which had been given the monkey antibody and which had been infected with a simian sister virus to HIV.
Fauci's lab is now completing a short study of vedolizumab plus ART in 17 patients and expects results by the end of October.
'The Devil You Know'
Many HIV/AIDS advocacy groups remain focused on cure research, and are grappling with the newly discovered impediments to shock and kill. All the same, remission without drugs is still a hot topic.
“I think a lot of people would like a remission,” said Jessica Salzwedel, who works in community literacy at the AIDS Vaccine Advocacy Coalition in New York.
She’s also seen a lot of excitement about long-acting injectable therapies, in which ART drugs are administered in a shot that can last four or eight weeks, instead of the regimen of daily pills patients now take.
Salzwedel feels people on ART may prefer the certainty of knowing HIV is being controlled rather than the question mark of going off ART during a research trial and waiting to see if the virus bounces back. For now, “It’s the devil you know versus the devil you don’t. Some people would rather live with a pill and know they are virally controlled.”
“We have to explore all avenues," summed up Fauci. "But I think remission is a very viable way to go.”
Anne-christine d'Adesky is a longtime chronicler of HIV research. Her 90s-era AIDS memoir, "The Pox Lover," was published in June.