Illustrations: Anatomy Blue

The Search for a Cure

Features

Research has turned HIV from a fatal infection into a chronic illness. Now, scientists want to liberate those living with the virus by subduing it for good.

By Wynne Parry

Come January, Xavier, who has HIV, plans to stop taking his daily medication — a pill that suppresses the deadly virus so effectively that standard tests cannot detect it in his blood.

“I’m nervous, hesitant, but at the same time, I’m curious to see the result,” says Xavier, who uses a pseudonym to protect his privacy.

If someone with HIV stops taking medication, the result is usually a foregone conclusion, and an alarming one. The virus that such pills suppress would return, bringing with it the specter of AIDS, a fatal condition in which a damaged immune system can no longer protect the body.

Four decades ago, an HIV infection was often a death sentence. Since then, advancements in medications known as antiretrovirals — regimens demonstrated in part by faculty now at Weill Cornell Medicine — have turned the fatal illness into a chronic but manageable condition.

Xavier, however, has a shot at keeping HIV at bay, even without his antiretroviral pill. In July, while continuing to take the medication, he received an IV infusion and began a series of injections, delivering an experimental treatment intended to subdue the virus for the long term, perhaps even permanently.

Early in 2023, as part of the procedure being tested in this clinical trial, he will stop his regular medication, and researchers will closely monitor his blood for evidence of the virus.

The strategy behind this trial draws inspiration from rare cases in which the human immune system fights off HIV all on its own. Known as “elite controllers,” these people can manage the infection without medication, pushing the virus to undetectable levels, perhaps even eradicating it entirely.

Through years of research, Dr. Brad Jones, associate professor of immunology in medicine at Weill Cornell Medicine, and his colleagues have developed an approach they hope will empower the typical immune system to perform more like an exceptional one when pitted against HIV. Xavier is among the patients who are volunteering to test it.

“I want it to be successful. That’s for sure,” he says of the experimental treatment. But after a lifetime of hearing HIV described as uncurable, he’s still “trying to wrap my brain around” the prospect of a cure.

“Possibly cured”

Science has driven tremendous progress in treating HIV. However, physicians still have no way to cure these infections. Researchers at Weill Cornell Medicine are among those leading the search for one. Some of their efforts, like the immune-augmenting approach that Xavier has volunteered to try, have advanced enough that they are being tested in people. Meanwhile, in more preliminary work, investigators are hunting for HIV’s hiding places within the body and for clues within the remnants of ancient human infections, all in the hopes of gaining crucial leverage against this invader.

Success can feel paradoxically close, yet distant. Since 2009, scientists appear to have cured a small handful of people. In five cases, leukemia or lymphoma patients with HIV have received dramatic treatments to resolve both conditions.

HIV and these cancers overlap in a crucial way: They attack blood cells or the blood-cell forming system. So, researchers decided to try treating both simultaneously by wiping out and replacing this system, either with new stem cells or bone marrow from a donor. All the successful transplants introduced a rare, natural genetic variation known as CCR5Δ32 that denies HIV entry into the white blood cells it likes to infect, rendering them impervious to any virus that remains.

In one of these cases, a woman who received a stem cell transplant at Weill Cornell Medicine has remained virus-free — without medication — for approximately two years. She is now considered “possibly cured,” according to Dr. Marshall Glesby, associate chief of the Division of Infectious Diseases at Weill Cornell Medicine, who is among the doctors caring for her. “There’s no clear definition of when you can say someone has been cured, but it’s looking very promising,” he says.

Regardless of how carefully researchers describe outcomes like hers, the same result remains out of reach for the vast majority of people living with HIV. Stem cell and bone marrow transplants entail a risk of dangerous complications, even death, that far exceeds the possible side effects of medications that can control HIV.

To cure everyone else, researchers need another approach, and they are exploring numerous possibilities.

“There’s a lot of work to be done. This is not something that’s going to happen six months from now,” Dr. Glesby says. Even so, he is cautiously optimistic. “Having the privilege of being a part of this woman’s journey, however, does give me hope.”

The power and the limits of antiretrovirals

While all human-infecting viruses must sneak into cells, HIV belongs to a group that goes deep undercover. These viruses slip into a cell’s instruction manual, its genome. Once there, such a virus can force the cell to manufacture more viruses, or it can lay dormant. With the right signal, however, some of these sleeping viruses can reactivate and make more HIV.

Depending on the type of antiretroviral, these drugs interfere with different steps in the process by which HIV forces a cell to copy it. But none can remove virus that has already inserted itself into cells.

Herman Morales, now 67, learned he had HIV in 1985, two years after the virus was identified as the cause of AIDS. Motivated by “basic survival,” he began enrolling in clinical trials to get access to what were then experimental treatments.

In the decades that followed, Morales lost many who were close to him, including his partner of 19 years, to the disease. But he stayed alive, “from one pill, one trial, to the next trial,” he says. “I’ve often asked God, why am I still alive when all my friends are dead? But here I am.”

The experience has exacted an enormous psychological toll. He describes being enveloped in depression and despair, fighting to keep his sanity. His body suffers too. Morales endures excruciating pain, spasms and numbness in his hands and feet, almost certainly the result of neuropathy caused by the older, harsher antiretrovirals he took in the past, according to Dr. Glesby, who treats him.

Even with treatment, an HIV infection still causes harm. Those living with the virus generally suffer more serious health problems and live slightly shorter lives than those who are not infected, underscoring the need for a cure.

Morales now takes four pills twice a day, an antiretroviral regimen beefed up to restrain his drug-resistant virus.

“I have to take the medications every 12 hours to keep the monster under control,” Morales says. “Sometimes it feels like you’re walking around and you’re carrying your own cage.”

A wild goose chase

That beast, however, has proven masterful at hiding.

When attacking the immune system, HIV favors infecting a certain variety of immune cells called CD4, or helper T cells. By hanging around in long-lived memory CD4 T cells, it appears able to maintain a presence for years. The virus has turned up elsewhere in the body as well — in other immune cells, and even outside the immune system.

Scientists still don’t have a firm handle on where HIV lurks while someone is taking medication, and, most importantly, from which of these hiding places it stages its return.

“If we were to know which particular cells drive the revival of the virus, then we would know where to go after them,” says Dr. Lishomwa Ndhlovu, a professor of immunology in medicine at Weill Cornell Medicine and a principal investigator of the $26.5 million HOPE Collaboratory, a multi-institutional NIH-funded group conducting research aimed at finding a cure. “That has been a big challenge to the field for the last 30 years.”

Researchers with the HOPE Collaboratory are looking for ways to identify the sleeper cells that harbor the virus and examining places within the body where it may find shelter from the immune system’s defenses. Meanwhile, members of its counterpart, the REACH Collaboratory, of which Dr. Jones is a principal investigator, are exploring how populations of virus-harboring cells change over time, and how some escape the immune system, even as they continue to produce new HIV.

As if to complicate the search, scientists have learned the vast majority of infected cells contain embedded HIV DNA that can’t replicate, either because of defects in its code or because it landed in the wrong spot in the genome. This discovery means scientists must not only find infected cells throughout the body, but also sift through them in search of those few containing competent threats.

Looking to “fossils”

Fortunately, the development of a cure may not depend on finding what Dr. Ndhlovu calls the “needle in the haystack.” Both groups are hedging their bets by simultaneously pursuing strategies they believe could succeed regardless of where virus hides out.

HOPE Collaboratory researchers are taking a multi-layered approach, with the primary objective of locking the dormant virus in place, leaving its DNA intact but trapped, like a bug under glass.

To accomplish this, they are taking cues from ancient viruses buried in the human genome.

HIV is far from the first virus to embed itself in our DNA, and remnants of similar, ancient infections litter our genetic code like fossils. Some have even found their way into our biology, contributing, for example, to the placenta and the brain’s ability to form memories. Most, however, are permanently silent, and all have lost their ability to cause infectious disease.

“If we think about curing HIV, there are different ways we can do it. The best is to get rid of HIV entirely, but maybe an intermediate step is to squash it into submission,” says Dr. Douglas Nixon, a professor of immunology in medicine at Weill Cornell Medicine. “If we can understand how we naturally control these ‘fossil viruses,’ then we might be able to extrapolate that to HIV.”

With this in mind, HOPE researchers are identifying potential drugs that could alter the expression of HIV’s genes, rendering the modern virus inert like its predecessors.

Dr. Nixon, meanwhile, continues investigating the changes evolution has wrought. Dr. Matthew Bendall, a research assistant professor in his lab, has developed a computational system the team is using to examine ancient viral remnants within CD4 T cells. How, they want to know, do these genetic fossils compare with HIV embedded within the same type of cells? Could these cells exert similar control over the modern infection?

Simultaneously, the collaboratory is exploring efforts to destroy, even remove, the virus from cells’ genomes using molecular tools, such as the genome editing system CRISPR-Cas9. Wrecking its DNA, says Dr. Ndhlovu, would be the “coup de gras” against HIV.

caged viron

Unleashing the immune system

While further along than the HOPE Collaboratory’s research, the clinical trial in which Xavier is participating takes a starkly different approach. Instead of seeking to interfere with the virus, it focuses on the virus’s counterpart and adversary, the human immune system.

When he enrolled, Xavier was no stranger to clinical research. He learned he had HIV while in his twenties, when he felt indestructible. “Well, that cracked that facade,” he says.

For about three months afterward, he grieved before making the decision to accept his diagnosis and move forward. “I was able to comfort myself through education,” he says.

He has since participated in about five studies, most recently the trial based on Dr. Jones’ research, which is being conducted through a partnership between the NIH-funded REACH Collaboratory, which Dr. Jones leads, and the AIDS Clinical Trials Group. Dr. Timothy Wilkin, assistant dean for clinical research compliance and a professor of medicine at Weill Cornell Medicine, and an infectious disease specialist at NewYork-Presbyterian/Weill Cornell Medical Center, is chairing the trial.

Scientists still don’t fully understand how the immune systems that belong to lucky elite controllers manage to fight off the virus. But they suspect their advantage lies in differences in their CD8 T cells, according to Dr. Jones.

“What gives me hope is the power of the immune system, when it’s properly unleashed,” he says.

While a postdoc roughly eight years ago, Dr. Jones and colleagues set out to find a way to force a confrontation between HIV and the immune system. They identified an immune signal called interleukin-15 that activates both CD8 T cells, which destroy infected cells, and their partners in arms called natural killer cells. Interleukin-15 also awakens HIV-infected CD4 T cells, and, in the process, prompts the virus they contain to begin replicating.

To develop the experimental treatment, they found a way to turn that signal up as loud as possible. They added a second boost, too, by administering broadly neutralizing antibodies, immune proteins which latch onto predictable parts of this shape-shifting virus. Once attached, antibodies act like labels, marking infected cells for natural killers to destroy.

Preliminary research suggests that, even though it does not wipe out the hidden virus, this two-part therapy may give the immune system the power to keep it in check over time.

“Through some mechanism that we don’t fully understand, the antibodies make the CD8 T cells more effective,” Dr. Jones says. In this way, they come to function more like those belonging to elite controllers.

Participating in this study has stoked Xavier’s optimism about the prospects for a cure. Even if this approach fails, he believes that, given the amount of research going on, something else will succeed during his lifetime.

“It’s like they are really throwing everything but the kitchen sink against the wall,” he says.

Fall 2022 Front to Back

  • From the Dean

    A Message from the Dean

    As an academic medical center, our tripartite mission is what drives us forward: we thrive on providing world-class care to our patients, making groundbreaking discoveries that are changing the future of medicine, and teaching the health care leaders of tomorrow.
  • Features

    The Search for a Cure

    Weill Cornell Medicine scientists aim to liberate those living with HIV by subduing the virus for good.
  • Features

    Evasive Action

    Could interrupting the evolutionary process of mutating cells hold the key to vanquishing cancer? Researchers led by Dr. Dan Landau are on the case.
  • Features

    New Frame of Mind

    Psychiatrist and neuroscientist Dr. Conor Liston (M.D. ’08, Ph.D.) and his team are poised to upend the way mental health disorders are diagnosed and treated.
  • Notable

    New Cancer Director

    Internationally acclaimed medical oncologist Dr. Jedd Wolchok, whose innovations in immunotherapy revolutionized melanoma treatment, was recently recruited as the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
  • Notable

    3 Questions

    Dr. Jay Varma, director of the new Center for Pandemic Prevention and Response, explains why an interdisciplinary approach is critical.
  • Notable

    Overheard

    Weill Cornell Medicine faculty members are leading the conversation about important health issues across the country and around the world.
  • Notable

    Notable News Briefs

    Faculty appointments, honors, awards and more — from around campus and beyond.
  • Notable

    Dateline

    In the global scientific effort to understand vaccine and natural immunity to SARS-CoV-2, Weill Cornell Medicine’s location in Qatar, a country of only a few million people, has been making an outsized contribution.
  • Grand Rounds

    Chiari Malformation

    When is Surgery Necessary?
  • Grand Rounds

    3 Questions

    Dr. Susan Loeb-Zeitlin, who worked with a multidisciplinary team to launch the new Women’s Midlife Program, shares insights about making menopause manageable.
  • Grand Rounds

    Social Impediments to Health

    The murder of George Floyd and the resulting national reckoning on race, along with the disproportionate impact of COVID-19 on communities of color, galvanized creation of the Anti-Racism Curriculum Committee at Weill Cornell Medicine.
  • Grand Rounds

    Grand Rounds News Briefs

    The latest on teaching, learning and patient-centered care.
  • Discovery

    COVID-19 and Diabetes

    Basic science and clinical investigations converge to offer answers.
  • Discovery

    Development of Schizophrenia

    Multiple changes in brain cells during the first month of embryonic development may contribute to schizophrenia later in life.
  • Discovery

    Findings

    The latest advances in faculty research, published in the world’s leading journals.
  • Alumni

    Profiles

    From taking the lead in newborn medicine to forging critical connections to move research from the bench to the bedside, our alumni are making an impact.
  • Alumni

    Notes

    What’s new with you?
    Keep your classmates up to date on all your latest achievements with an Alumni Note.
  • Alumni

    In Memoriam

    Marking the passing of our faculty and alumni.
  • Alumni

    Moments

    Marking celebratory events in the lives of our students, including Match Day, the White Coat Ceremony and Graduation.
  • Second Opinion

    A New Lens

    What’s one way that medical education must change to better address health inequities?
  • Exchange

    Pivot Points

    Two women leaders at Weill Cornell Medicine whose professional paths have connected discuss the power of mentorship — for themselves and other women in academic medicine.
  • Muse

    Two Forms of Truth

    Dr. Laura Kolbe, whose poetry has garnered notable honors, talks candidly about how her writing helps her build a bridge to her work as a clinician.
  • Spotlight

    Building Connections

    Dr. Kathleen Foley (M.D. ’69) has been bringing people together throughout her expansive career as a specialist in pain management and palliative care for cancer patients.