13:55, 29.Jun 2018
The road to a cure for HIV is long, winding, and with no definite end in sight.
That said, a new study published last month in the journal Nature is shedding light on a way to measure what is considered an inactive form of the virus that rests hidden in people’s cells.
This so-called “latent reservoir” of HIV has stood as a roadblock to eradicating the virus, stubbornly staying put despite being attacked by increasingly sophisticated antiretroviral drugs used to treat the virus.
For researchers in the HIV cure field, this new technique is a significant development because it offers a clearer look at how to pinpoint this viral reserve.
Why is this important?
Past tools are said to have greatly overestimated how much of this under-the-radar cache of virus existed in any given cell.
Now, measuring the reservoir to see how it responds to experimental therapies may be less of a shot in the dark.
The ‘latent reservoir’
This new work comes out of the Maryland lab of Howard Hughes Medical Institute investigator Dr. Robert F. Siliciano, PhD, a leader in the HIV cure world. He said that while current drugs out there are doing a good job of attacking and suppressing the virus, none of them are able to get rid of this persistent latent form.
Over the years, Siliciano and his colleagues have attempted various methods to try to get around this problem, essentially “waking up” the latent virus and killing the bad actor cells.
He said, while there are a lot of clinical trials underway to do this, you won’t know whether or not they’re working unless you can clearly measure this drug-resistant reservoir.
“Measuring the latent form is going to tell us whether we are closer to a cure or not,” Siliciano, professor of medicine at the Johns Hopkins University School of Medicine, told Healthline. “You can’t know whether you are making progress unless you can measure before and after an intervention and say ‘Aha, this went down.’ “
Siliciano said that in clinical trials of new antiretroviral treatments, researchers would see just how much the presence of the virus dropped, and whether or not the drugs themselves produced this decrease.
“It really accelerates the development of antiretroviral therapy if you have a simple assay (a lab test used to analyze the effectiveness of a drug, for instance) that measures the key quantity that indicates how much virus is there,” he added. “It should be very helpful.”
How HIV attacks cells
For those unfamiliar with how HIV attacks a body’s cells, the idea of a hidden stash of the virus evading the attacks of drugs can sound hard to grasp.
Basically, HIV treatments consist of a combination of drugs that hit the virus at a specific stage of its lifecycle. If drugs cut the virus off at two or more of these stages, the virus can’t make copies of itself. It then cannot be detected in a person’s bloodstream.
In 2017, the Centers for Disease Control and Prevention (CDC) announced that people with HIV who strictly stick to their antiretroviral therapies, can reach this “undetectable” viral count.
This means they’re unable to transmit the virus to their sexual partners. While current treatments mean people with HIV can lead healthy, long lives, this isn’t a cure.
The latent reservoir remains stowed away in the genes of CD4 cells, which are what HIV infects.
People who hit “undetectable” status must remain on their antiretroviral drugs because, even when infected CD4 cells go dormant, they hold on to their genetic record of the virus. You might say they’re in hibernation. If a person goes off their treatment, the infected cells wake up and the stored HIV information generates new viruses.
Attempts to measure the reservoir
In 1995, it was Siliciano’s lab that first officially showed the existence of the reservoir itself. That research was published in Nature, too.
Since then, efforts to effectively measure the reservoir have mostly been trial and error. Dr. Una O’Doherty, PhD, associate professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania
at the Perelman School of Medicine, told Healthline that before the advent of antiretroviral therapy, it was fairly easy to measure a person’s HIV viral load and CD4 count.
Now, with therapies leaving many with such low amounts of the virus that it’s undetectable, it’s hard to come up with an accurate measure.
She explained that the majority of HIV in the human genome — or proviruses — becomes damaged, most likely due to the virus’s inaccurate replication cycle.
Given that so much of this damaged HIV DNA is in the bloodstream of infected people, it’s difficult to sometimes parse the defective HIV from the latent reservoir of HIV genomes that have the potential to make new, active viruses.
Research out of Siliciano’s lab by Dr. Ya–Chi Ho, PhD, assistant professor of microbial pathogenesis and medicine at Yale School of Medicine, revealed 93 percent of all proviruses are damaged and defective, which offers up a confusing smokescreen of sorts for scientists in trying to find this reservoir.
“It feels very much like looking into the darkness,” O’Doherty said. “When you are testing clinical trials, did these measures of HIV DNA increase or decrease? Some people would take patients off therapy to try to measure how fast the virus didn’t come back. Over those two decades, we fought with each other what is the best way to measure this. Everything fell short, in my opinion.”
O’Doherty said sequencing the mass of proviruses in an infected person is heavily labor intensive. She said the field has to “get much better at processing big data” if it can effectively do this.
Satish K. Pillai, PhD, associate professor of laboratory medicine at University of California, San Francisco (UCSF), told Healthline that better understanding and quantifying the latent reservoir is the “heart and soul of where the HIV cure field is going.”
He said his own lab right now is working on quantifying the size of the reservoir and trying to “biologically characterize the latent cells” and how they look different from unaffected cells and “productively infected cells.”
“This is another challenge in the field, knowing more about how latently infected cells look. If you know how they look, you have a better chance to actually destroy them,” Pillai said. “We have a limited understanding of how latently infected cells behave in vivo (in an actual person). We don’t have much information on how they are different from productively infected cells in actual infected human beings. The reason being is that the cells hang out for so long with the virus sitting in them, so that they are immunologically invisible.”
He said that increasingly more research suggests that “signature characteristics” of cells with HIV should allow researchers to eventually be able to identify them mixed in with a population of the defective cells.
“Right now, our lab is using a lot of approaches to drill deep down to see how these latently infected cells look different from their neighbors, to identify biomarkers and molecular mechanisms in cells allow the virus to be in this latent pharmacological state in infected cells,” Pillai explained.
The need for a cure
Siliciano said we can’t really say that we can see a “light at the end of the tunnel” when it comes to an actual HIV cure. But, this research gives scientists a step in the right direction in better measuring HIV levels in the human body.
The need for a cure is certainly there. Since the start of the HIV/AIDS epidemic, more than 70 million people have been infected with HIV and about 35 million have died from it.
Right now, countries in sub-Saharan Africa are most impacted. The World Health Organization reports that, in the region, one out of every 25 adults live with HIV.
Domestically, about 1,122,900 adults and adolescents in the United States were reported to have the virus by the end of 2015, according to the Centers for Disease Control and Prevention.
“The new study and this method is an incredibly elegant and intuitively interesting and promising approach,” Pillai said of Siliciano’s research. “At end of day, we need to see if this approach can actually tell us anything — can this approach predict something in the clinic that we care about?”
He further explained, “What we care about is what happens when the antiretroviral treatment stops. Can we use this approach to characterize the genetics of HIV in a clinical sample, and make reasonably accurate predictions about how long it’s going to take for the virus to come back?”
O’Doherty said it will be interesting to see what happens once Siliciano’s method starts being applied widely in HIV research labs.
“I want to reinforce something — I don’t think the study makes ‘a cure’ more possible,” she stressed. “I think it makes it more possible to reevaluate trials. But I think that’s huge. We were caught being in the darkness and now we will have a better understanding.”