A brief history of curing viral infections in humans
Almost as soon as HIV was identified in 1983 as the cause of AIDS, the clamor for a cure for this insidious viral infection began. The repeated failures and numerous tales of human tragedy that followed gave rise to a sense of unattainable loftiness reserved only for distant dreams, not reality. This sense of unattainability was shattered in 2007, with the initial reports of Timothy Brown—the Berlin patient—the only person to have ever been cured of HIV. The door was cracked opened at last; we were on our way. Right?
Maybe not so fast. Let’s take a small dose of reality and look carefully at our medical track record for curing viral infections. In 1983, modern medicine had rarely ever cured a life-threatening viral infection, except perhaps herpes simplex (HSV) encephalitis (brain infection), initially with the old chemotherapy agent vidarabine and later with the more effective and less toxic acyclovir. But even in those cases, the virus causing the serious infection, while significantly tamped down and put into latency, was still able to recur in the surviving person’s future. It was not eradicated. Since those early days, successful suppressive treatments for many members of the herpes family of viruses [HSV-1 & -2, VZV (chicken pox/shingles virus), CMV (retinitis, colitis), EBV (infectious “mono” virus)] have been developed to suppress these potentially life- and sight-threatening viral infections, but not to cure them.
The biggest breakthrough in truly curing a viral infection came only within the last 10 years with the development and approval of many all-oral, non-interferon-containing, single-tablet regimen (STR) combination treatments for hepatitis C (HCV). Currently 90–100% of persons with almost any type of HCV, at any stage of liver disease or treatment history, with or without HIV can be cured of this infection with 8 to 12 weeks of a one-pill-once-a-day treatment. The chances of cured HCV infection coming back is very, very low, unless the cured person re-engages in high-risk behavior for acquiring the infection.
So, why was HCV so “easy” to cure and HIV not so?
First, it is important to point out that HCV became curable based upon essential new scientific knowledge that came from research discoveries on HIV treatment. The four classes of direct-acting agents (DAAs) that have revolutionized HCV treatment to create a cure are heavily based upon scientific discoveries about viruses made while scientists were studying HIV. Second, there is a big difference between the two viral infections, which makes them very different targets for cure—HCV does not “integrate” or insert its genetic material into the DNA of human cells that it infects like HIV does to the human cells which it infects. Eradicating non-integrated HCV genes from a human cell is much easier than the task of cutting out integrated HIV genes from an infected human CD4+ T cell. When HIV “splices” its genetic material into the DNA of human cells, its genes continue to be carried in those cells and all “daughter” cells that come from those cells for as long as they live. Thus, the challenge of curing an integrated viral infection like HIV is a much higher bar.
But wait, what about our highly effective antiretroviral therapy? Why isn’t it enough to cure HIV?
It’s certainly true that our current antiretroviral treatment (ART) is highly effective and has greatly diminished the death and destruction that HIV has waged on humans in many parts of the world. But these agents have important limitations. First, they can only work when virus is in its “actively replicating” phase—that is, when it is churning out large numbers of new infectious viruses to travel throughout the body to infect new cells. Second, when virus enters its latent, or “sleeping,” phase, antiretrovirals are no longer effective against the dormant, integrated virus that has been spliced into human CD4+ T cells. It is, in fact, this phase of HIV infection that makes up the often spoken about “latent viral reservoir,” which is referring to those pieces of viral genetic material quietly sleeping inside of human immune cells (CD4+ T cells), that has the potential to reactivate and produce new viruses which can infect new cells. Fortunately, the number of these latently infected cells is small. It is estimated that only 1 to 60 per 1 million CD4+ T cells are latently infected with HIV. Even though this “1-in-a-milion” or so number sounds very small, it is enough to allow HIV to re-emerge in the blood of people living with HIV (PLWH) who stop their HIV medications after being undetectable for many, many years. And this generally happens within 4 to 8 weeks after stopping antiretrovirals in most PLWH on ART. Thus, this is our formidable, final hurdle between us and a cure for HIV.
Scaling the final hurdle of the latent viral reservoir
HIV researchers usually fall into two basic camps: the immunologists—the scientists who are experts on our incompletely understood human immune system which protects us from both foreign invaders (infections) and internal invaders (cancer)—and the virologists, those scientists who are experts on every aspect of how viruses reproduce themselves and cause disease, and then finding their “Achilles’ heels” to attack and stop them from doing harm. We owe a great deal to the virologists for much of the success of combination ART.
When we think about curing HIV, many tough scientific questions are directed to both virologists and immunologists.
The virologists will help us better understand and discover holes in the way that HIV goes into its latent (or sleeping) phase so that we can use that information to shock it awake and attack it, lock it in that phase for good, or prevent it from going latent in the first place. They will discover ways to protect CD4+ T cells from being susceptible to HIV; that is, to make them “uninfectable,” by blocking the entrance sites that HIV uses to enter and infect T cells.
Finding creative ways to use “gene editing” technology to cut out the integrated HIV genes from the DNA of CD4+ T cells to free them from viral control will also be one of the virologists’ goals. Gene therapy, the science of adding, deleting, or blocking genes within the human DNA, is still in its infancy for treating human disease; however, at least one gene therapy has been approved by the FDA as treatment for a childhood cancer.
Many of these areas of research are already well underway; some have shown promise, others have not and are being abandoned, and still others have already “gone back to the drawing board” for a second or third revision and re-try.
Immunologists will help us better understand how we can create “new immunity,” or resistance against HIV in PLWH who did not have that immunity when they first encountered the virus and became infected. In other words, they will help us learn how to retrain or rebuild the immune systems of PLWH to become HIV-resistant without ART.
With previous serious viral infections, such as polio, small pox, and measles, many people became infected but survived the infection without treatment. This observation told us that the human immune system could be re-trained or re-engineered to resist those viruses.
The ability to “train” the human immune system to resist viral infections has become a commonly used and effective preventative force against viral infections—better known as vaccination or immunization. In fact, immunization against viral illnesses has been the major way that we have controlled these infections for the last 150 years.
Unfortunately, there are no known human beings who have developed long-term, natural immunity against HIV. So, we do not have a proven natural pathway to follow as we have had with other viral infections. (Elite and viremic “controllers,” those PLWH who have undetectable viral loads or less than 2,000 copies/mL without ART, are our closest guides to how humans can naturally resist HIV. Unfortunately, it is estimated that only 1% to 3% of PLWH fall into the controller category.)
How to best create new immunity for PLWH is going to be a challenge the likes of which human medicine has only overcome once before. That previous life-saving treatment is for advanced cancers (lymphoma, leukemia) that could not be cured with usual chemotherapy and radiation therapy.
That treatment is called stem cell transplantation. It involves taking the youngest, freshest cells of the immune system, called stem cells, from the bone marrow of the same person (for lymphoma) or from another person (for leukemia) and giving them to the person with cancer. This is done after all cancer (and immune system) cells of that person have been destroyed with large doses of chemotherapy and radiation therapy. In other words, the cancer and the immune system of the person are first destroyed and then replaced with healthy new immune cells. The slate is wiped clean of cancer and a new, healthy immune system is rebuilt.
This is the process that Timothy Brown underwent to cure his leukemia, and as an added benefit, cured him of HIV. However, the risk of destroying a person’s immune system and replacing it with a new, cancer-free one is only balanced by the benefit of not dying from an otherwise fatal cancer. The risk-to-benefit ratio of using stem cell transplantation as a cure for both cancer and HIV has been positive, but in only 1 of over 10 attempts.
Is Timothy Brown’s story enough to urge other PLWH to take on this risk? Certainly, if they have lymphoma or leukemia unresponsive to treatment, but what about PLWH without cancer?
Another potentially promising immune-boosting therapy already approved for cancer treatment and sometimes cure is a new class of medications called immune checkpoint inhibitors (ICIs). These human antibody treatments are aimed at reviving “overstimulated” and “exhausted” T cells which have been turned off by a natural immune shut-off valve. ICIs are designed to block this turn-off switch, a state commonly found in T cells in PLWH, and thereby turn the immune system back on.
Using one’s own revitalized T cells to fight one’s HIV makes good sense, right? While these treatments have shown promise in many cancers, they can also potentially cause the immune system to attack non-HIV-infected cells and cause long-term side effects such as low thyroid hormone levels, requiring the affected person to take thyroid hormone replacement for life.
Here again, are the now proven positive treatment results in persons with cancer adequate to explore these therapies in PLWH?
Are we ready for a cure for HIV? Of course we are, aren’t we?
A growing number of research publications, from several parts of the world, written almost exclusively by PLWH and other community advocates, have documented the PLWH community’s ever vigilant, but hopeful, attitudes, feelings, fears, and aspirations for a cure for HIV. In addition to providing a cogent, irreplaceable voice for the persons central to this entire discussion, these publications have reflected the need for continued frank discussion and education for both the research and PLWH advocacy communities to improve communication and avoid misunderstandings.
For example, it has been reported that PLWH prefer the term “eradicating” rather than “sterilizing” when describing a cure that will remove all traces of HIV from a PLWH’s body. This justifiably stems from the negative fertility connotations associated with the term “sterilizing”. Further, PLWH prefer an “eradicating” versus a “functional” cure (ART-free remission from HIV without all traces of the virus removed but rather held in check by new anti-HIV immunity) due to concerns that the virus may return and become resistant to ART. From a scientific/medical standpoint, expectations of a truly eradicating cure may be too high and unattainable. The best outcome that medical science has ever accomplished in treating infectious diseases among humans has been to decrease the amount of infection to a level that the immune system can control it for a lifetime, or at least many years. Infections are rarely, if ever, truly eradicated from humans. It’s the immune system that is “trained” to do the work.
It goes without saying that a renewed, reinvigorated, and mutually respectful partnership is needed between the PLWH and scientific/medical communities as we all embark on our greatest challenge to date—to cure HIV. Exceptional, new, out-of-the-box thinking and exquisitely refined new takes on old ideas will be needed as the journey unfolds. Voluntary altruism, once so evident and proudly practiced in the earlier years of the epidemic, will be encouraged and respected. Carefully worded, clear, and trusting communication, both oral and written, using language comfortable for all involved will be the order of the day. Borrowing from the lessons learned from the days of drug development of our currently available ART, successful cure strategies will most likely be given as combination treatments, perhaps in series, perhaps together. Unlike those drugs which are primarily oral and tablet-based, cure strategies may well involve more procedures, intravenous infusions, and longer periods of follow-up to see if they work. There is no doubt that the rationale for, the desire for, and the understanding of what a cure for HIV means will be different and perhaps unique to everyone involved, but the common purpose for treading this uncharted road together will make it bearable and successful.
W. David Hardy, MD, is Adjunct Professor of Medicine, Division of Infectious Diseases at the Johns Hopkins University School of Medicine.