‘Repliclones’ fuel perplexing persistence of HIV in the blood of some patients on therapy

Increasingly, UPMC’s chief of infectious diseases—a well-regarded expert in HIV/AIDS—is contacted by a perplexed physician describing a patient with HIV who insists they are adhering to the daily medication regimen meant to keep the virus in check, but testing says otherwise.

Virus is still showing up in the patient’s blood, something clinicians believe can’t happen when the infection is controlled with medication. University of Pittsburgh School of Medicine scientists report today that they’ve solved the mystery—and the answer has clinical implications.

In a study published in the Journal of Clinical Investigation, Pitt infectious disease researchers show that the issue isn’t nonadherence to medication or resistance to the drugs. Instead, the patients are victims of what the scientists have dubbed “repliclones”—large clones of HIV-infected cells that produce infectious virus particles.

“We found that repliclones can grow large enough and produce enough virus to make it appear that antiretroviral therapy isn’t working completely even when it is,” said senior author John Mellors, M.D., who holds the Endowed Chair for Global Elimination of HIV and AIDS, and is chief of the Division of Infectious Diseases at Pitt and UPMC.

HIV replicates by taking over a cell’s machinery and using it to produce more virus, which can then go on to infect other cells. Antiretroviral therapy, which is taken daily, prevents the virus from infecting new cells so that even though HIV can’t yet be cured, it can be controlled to the point that it isn’t detectable in blood tests.

Elias Halvas, Ph.D., research assistant professor in Pitt’s Division of Infectious Diseases, and Mellors led a multidisciplinary team of U.S.-based HIV scientists in investigating the medical records and blood from eight patients with non-suppressible HIV viremia—detectable virus in the blood—despite adherence to antiretroviral medications. Repeated samples of each patient’s blood revealed identical viral genetic sequences that did not change over time.

“This indicates that, in the individual patients, the virus in their blood was coming from identical cellular factories,” said Halvas.

In short, rather than the virus going out and infecting new cells, already infected HIV-producing cells are growing into large clones that make and release virus. Current medications for HIV infection block the virus from infecting new cells but don’t affect virus production from cells or clones of cells that are already infected.

“Even though we don’t have evidence that the virus produced by these repliclones is then infecting new cells—which would be detrimental to the patient’s immune system—they could cause other problems, such as chronic inflammation,” said Mellors, who also is Distinguished Professor of Medicine at Pitt. “If the patient were to stop drug therapy, the virus could have a head-start on rebounding. And repliclones are a key barrier to developing a true cure for HIV.”

The immediate implication of their discovery, Mellors said, involves informing clinicians and patients that HIV viremia can be caused by repliclones. This can help clinicians in developing disease management plans that may allow continuation of current antiretroviral regimen, knowing that switching the treatment may not suppress the viremia. Instead, the patient can be monitored over time for changes in the level of viremia, which can decline as the repliclone shrinks or sometimes can stay the same or increase slowly. Large increases in viremia should prompt the review of medication adherence again and exclusion of new drug resistance, Mellors added.

For the long-term, scientists must figure out how repliclones escape the immune systems and how they can be efficiently killed to cure the infection. While more research is needed, Mellors and his team speculate that smaller, less easily detected repliclones may be present throughout the body and be responsible for the rapid rebound of HIV in patients who stop their therapy. An added complexity is that all the cells of a repliclone may not all be making virus at the same time and thus remain hidden from the immune system as a latent or invisible reservoir of HIV.

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I’ve been questioning my sexuality for years and really think I’m asexual. I don’t feel safe coming out and feel like I can’t tell my doctor or even my family right now. If I tell my therapist, will they be understanding, and will it be confidential?

Thanks for your question. We know that a person’s sexual attraction can range from being asexual, attracted to females, attracted to males, or a combination of females and males. This attraction may stay constant throughout a person’s life or may change.

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Potential target identified for migraine therapy

Migraines affect millions of people worldwide, often lasting days and severely disrupting lives. More than simply super-intense headaches, some migraines actually result from pathological excitation of neurons in the brain. A new study in mice led by Kohichi Tanaka at Tokyo Medical and Dental University (TMDU) shows that susceptibility to migraines could be related to a molecular transporter that normally works to prevent excessive excitation of neurons.

Neurons in the brain communicate with each other by passing along molecules called neurotransmitters. After a neurotransmitter takes care of business, it is transported away from the synapse—the space between two neurons—so that it cannot be used over and over again. This process is called reuptake, and is one of many ways in which over-excitation of neurons in the brain is prevented. Migraines are related to a condition called cortical depression, in which a large wave of hyperactivity spreads across the brain, followed by a wave of inhibition, or depressed brain activity. Tanaka and his team hypothesized that susceptibility to cortical spreading depression is related to disrupted transport of glutamate, the most common excitatory neurotransmitter.

In turns out that mammals have four molecules that transport glutamate, and three of them are in the cerebral cortex. To determine which of these, if any, is related to cortical spreading depression, the researchers created three strains of knockout mice, each of which lacked one of the three cortical glutamate-transporter genes. They found that when mice lacked the GLT-1 transporter, cortical spreading depression occurred more frequently and spread more quickly than in control mice or in the other knockout mice.

“We know that 90% of glutamate is transported by GLT-1 back into astrocytes, not neurons,” says Tanaka. “Our findings thus highlight another important function of glial cells in the brain as they support neuronal function.”

To confirm their findings, the team then measured the amount of glutamate outside of cells using a platinum-iridium electrode coated with glutamate oxidase. When glutamate oxidase interacts with glutamate, it creates a negative current that can be detected by the electrode very quickly, allowing almost real-time measurements of glutamate concentration in the region.

“A fast biosensor is critical,” explains Tanaka, “because cortical spreading depression only lasts about 5 minutes, and the changes in glutamate concentration could never be found using conventional methods that take minutes to hours of sampling.” When testing the three knockout mice, only the GLT-1 knockout mice produced current that differed from that of the control mice. This means that the greater and faster accumulation of glutamate outside of neurons resulted from impaired uptake by astrocytes.

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I’m a homeschooler, and things at home are getting rough. I’m stressed all the time, but I don’t feel like I can tell my parents. I don’t have outside resources. How do I get counseling without them knowing?


We are sorry to hear things have been difficult at home. With COVID-19 precautions, so many young people are feeling stuck at home and many are struggling with challenging family situations. Your ability to access counseling without parental knowledge depends on where you live. Some states in the USA allow 16-year-olds to engage in therapy without their parent knowing. It may be worth having a conversation with your parents about your desire for additional support. Your primary care doctor can help you with this conversation. If talking to your parents is not an option, you can access crisis resources such as the Crisis Text Line (text HOME to 741741), which is free and private.

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Emergency departments slow to adopt proven opioid use disorder therapy

A new study by Yale researchers looking at nearly 400 clinicians at four urban academic emergency departments found that, despite scientific evidence supporting the benefits of buprenorphine for opioid use disorder, just 21% of emergency department clinicians indicated readiness to offer it to patients in need.

The study, which appears in the May 11 issue of JAMA Network Open, involved emergency departments at Mt. Sinai Hospital in Manhattan, the Johns Hopkins Hospital in Baltimore, Harborview Medical Center in Seattle, and University of Cincinnati Medial Center.

The study is the first installment in Project ED Health, an implementation study funded by the National Institute on Drug Abuse Clinical Trials Network to support strategies for increasing buprenorphine prescriptions in emergency departments. Buprenorphine, a partial opioid agonist—a drug that activates opioid receptors in the brain to a lesser degree than oxycodone and morphine—is safe to administer, relieves withdrawal symptoms, and can prevent overdose, according to years of established medical research. An implementation study reveals barriers to adopting research findings.

Project ED Health is led by two Yale physician-researchers, Dr. Gail D’Onofrio, professor and chair of the department of emergency medicine and Dr. David Fiellin, professor of internal medicine and director of the Yale Program in Addiction Medicine.

“This study provides a baseline evaluation of what care emergency departments are providing to patients with opioid use disorder,” said lead author Dr. Kathryn Hawk, assistant professor in emergency medicine and attending physician in the Yale New Haven Hospital Emergency Department.

Despite barriers, clinicians are willing to give buprenorphine to patients in the emergency department, provided that they receive sufficient support and training, the study found.

“The willingness of emergency department providers to take on a new treatment is changing drastically,” said Hawk.

Researchers conducted the study between April 2018 and January 2019. A team of addiction medicine physicians met with providers at the hospitals, including doctors, advance practice providers (APPs), and emergency medicine residents. Providers participated in a web-based anonymous survey that collected data about their demographics, training, experiences with ED-initiated buprenorphine, and readiness to administer buprenorphine for opioid use disorder on a scale of one to 10. Providers then rated their work culture, clinical experience, and perceived patient needs. Later, the study team ran focus groups to better understand factors impacting buprenorphine prescribing in the ED.

The researchers found that barriers to providing buprenorphine included lack of formal training, limitations on time, limited knowledge of local treatment resources, absence of local protocols and referral networks, and perceptions that initiating buprenorphine therapy falls outside the scope and practice of emergency medicine.

One resident physician quoted in the study said: “Trying to suss out which of those patients might be appropriate for initiating some therapy and which aren’t is a skill that I don’t have. I don’t think that it’s a skill that we’re necessarily being trained for right now.”

There was also confusion about required waivers. Just 3% of providers interviewed had DATA 2000 (x-waiver) training for buprenorphine. Providers need the waiver, which requires eight hours of approved training for physicians and 24 hours for APPs, to write a prescription for buprenorphine to be filed at a pharmacy. Emergency providers can give buprenorphine in the ED without the special waiver, said Hawk, but added that they “needed clarification around what they can and can’t do.”

Historically, emergency departments have not been thought of as places where patients are treated for opioid use disorder, she said. Typically, those patients were referred to outpatient clinics for treatment.

“The opioid epidemic has really changed that,” Hawk said.

In 2015, Yale researchers published a landmark study in JAMA that found that patients admitted to emergency departments for opioid use disorder who were treated with buprenorphine along with medical management in primary care were twice as likely than patients not given buprenorphine to remain in addiction treatment one month later.

“The big message of that study was that initiating treatment in the ED setting was very effective,” said D’Onofrio, “but true adoption lagged. So now we’re trying to understand why that is, and how we can improve implementation of this best practice.”

This latest study found that in order to improve adoption of ED-initiated buprenorphine there needs to be more education and training, established protocols, and enhanced communication across different stakeholder groups.

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