By W. David Hardy, M.D.

Brief history about curing viral infections in humans

Almost as soon as HIV was confirmed as the cause of AIDS in 1983, the clamor began for a cure for this insidious viral infection.

Yet repeated failures to achieve a cure and decades of human tragedies that followed gave rise to a sense that a cure was unattainable. That grim conclusion was shattered in 2009 with the initial reports of the first-cured, Berlin patient, Timothy Ray Brown. The door was cracked opened at last.  We were on our way, right?

Maybe, but not so fast. Let’s take a small dose of reality and look carefully at our medical track record for curing viral infections. The biggest breakthrough in successfully curing a viral infection came only within the last 12 years with the development and FDA approval of several treatments for the hepatitis C virus (HCV).

Currently 90%-100% of persons with almost any type of HCV, with 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 a cured HCV infection coming back is very, very low, unless the cured person re-engages in 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 was cured based upon essential new scientific discoveries that came directly from research on HIV treatment. 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 genes into the DNA of human cells which it infects like HIV does.

Eradicating non-integrated HCV genes from a human cell is much easier than the task of cutting out integrated HIV genes from a 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 “daughters” 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 changed the longevity and quality of life of persons with HIV throughout the world who have access to ART.  But these medications have important limitations.

First, they can only work when the virus is “actively replicating”; that is, when it is churning out large numbers of new infectious viruses to travel throughout the body to infected new cells.

Second, when the virus enters its latent or “sleeping” phase, these medications are not effective against the quiescent, latent, integrated virus 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”:  copies of viral genetic material quietly sleeping inside of CD4+ T cells which can reactivate, produce new viruses and 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 persons with HIV when they stop their HIV medications for as little as 1-2 months. Thus, this latent viral reservoir is our formidable, final hurdle between our current state of treatment and a cure for HIV.

Scaling the Final Hurdle of the Latent Viral Reservoir

HIV researchers often fall into two camps. First, the virologists: the scientists who are experts on every aspect of how viruses reproduce themselves, cause disease and are vulnerable to attack by identifying their “Achilles’ heals” to stop them from doing harm.  Second, 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).

The virologists will help us to discover how and why HIV goes in and out of its latent or sleeping phase so that we can use that information to shock it out of that phase 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 “infection-resistant” by blocking the entrance sites that HIV uses to get into T cells.

Finding creative ways to use “gene editing” technology to “cut out” the integrated HIV genes from the DNA of human 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 human DNA, is still in its infancy for treating human disease. 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.

The immunologists will help us to better understand how we can create “new immunity” or resistance against HIV in persons who did not have that immunity when they first encountered HIV. In other words, they will help us to learn how to retrain or rebuild the immune systems to become HIV-resistant without HIV medications.

With previous serious viral infections, like polio, smallpox, measles and even Ebola, many people became infected and survived the infection without treatment. This informed us that the human immune system could be taught how to resist those viruses. “Training” the human immune system to resist viral infections has become a frequently used and effective means of fighting infections – better known as vaccination or immunization. In fact, immunization against viral illnesses has been the almost singular way that we have controlled these infections for over 200 years and still do today.

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. How to best create new immunity for persons with HIV is going to be a challenge the likes of which human medicine has only accomplished once before. That life-saving treatment — stem cell transplantation — is for advanced cancers (lymphoma, leukemia) which could not be cured with usual chemotherapy and radiation therapy. 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, both the cancer and the immune system of the affected person are first destroyed and then replaced with healthy new immune cells. The slate is wiped clean of both cancer and the old immune system, and a new, healthy immune system is re-installed. This is the process by which the three formerly HIV+ persons have been cured of both cancer and HIV.

The risk of destroying a person’s immune system and replacing it with a new, cancer-free immune system is currently only balanced by the benefit of not dying of an otherwise fatal cancer. The risk-to-benefit ratio of using stem cell transplantation as a cure for both cancer and HIV has not been overwhelmingly positive.  This process has been used in over 30 other persons with HIV without success. Are these three success stories enough to urge other persons with HIV to take on this risk? Certainly, if they have lymphoma or leukemia that is unresponsive to treatment, but what about person with HIV without cancer?

Are We Ready for a Cure for HIV? Of Course, We are, Aren’t We?

A growing number of publications written almost exclusively by persons with HIV and/or community advocates have documented the HIV+ community’s ever-vigilant, but hopeful attitudes, feelings, fears and hope 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 a need for frank discussion and education for both researchers and the HIV+ communities to improve communication and avoid misunderstandings. From a scientific/medical standpoint, expectations of a truly eradicating cure may be too high and unattainable.

The best, most common outcome that medical science has ever accomplished with treating infectious diseases in humans has been to decrease the amount of the 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 completely eradicated from humans. It’s the immune system that does the lifelong surveillance, identification and elimination once the infection has become reduced or weakened enough.

It goes without saying that a renewed, re-invigorated and mutually respectful partnership is needed between persons with HIV and scientific/medical communities as we embark on our greatest challenge to date — to cure HIV. We will need exceptional, new, out-of-the-box thinking and ideas as the journey unfolds.  We will need to encourage the bravery and altruism of volunteers in clinical trials to return, like the frequent and proud practice in the early years of the HIV epidemic.

As with our currently available anti-HIV medications, successful cure strategies will most likely be given as combination treatments — perhaps in series, perhaps together. Unlike these current treatments which are primarily based on oral tablets or, more recently, injections, cure strategies will likely involve more procedures, intravenous infusions and longer periods of evaluation to see if and how they work.

Although the different groups with a stake in a cure (e.g., patients & their families/loved ones, pharmaceutical companies, and governmental and private researchers) have different reasons for working towards the same goal, the common purpose for treading this uncharted road together will make it bearable and, we hope, ultimately successful.