Towards an HIV Cure

In the past several months, there have been some highly publicized stories of individuals being “cured” of HIV. I put cured in quotes because these are case reports “functionally cured” … meaning after treatment has been withdrawn, the virus cannot be detected. There’s no way of knowing with 100% certainty that there isn’t at least one latent copy somewhere in the patients’ bodies. This is because of the nature of HIV and retroviruses in particular. The virus integrates its genome into the host’s genome. It can remain there dormant for years or the remainder of the host’s natural life without causing problems. While it is dormant, the host cells can themselves divide and replicate and expand what is known as the “viral reservoir.” At some point, many years down the line, the virus could be reactivated by some event (or from random chance) and what was just a single integration event …. could be thousands of cells producing new viral particles. So the only way to be 100% certain that someone is cured of a retrovirus is to check the genome of each and every susceptible cell and determine that it does not contain integrated latent virus. This isn’t really possible with a living person, so the best we can say is that someone continues to live “functionally cured.”

HIV Life Cycle. Current drugs prevent functioning of viral entry, reverse transcriptase, integrase, and protease. It does not prevent DNA replication via normal cell cycle of a latently-infected cell; which was what “eradication” therapy would target.

There are two ways that people were functionally cured of HIV. The first case was known as the “Berlin patient” who was infected with HIV but also had acute myeloid leukemia (very serious white blood cell cancer) and the treatment required full body irradiation to kill off all of the white blood cells and bone marrow (haematopoetic) cells followed by bone marrow transplant, an incredibly risky procedure. He survived and remains functionally cured of HIV. The most recent case is a similar case of irradiation and bone marrow transplant.

The second way that an individual was functionally cured was an infant who was infected by in utero exposure from a mother who was infected. The doctors caring for the infant knew of the mother’s and infant’s HIV status and quickly got the infant started on highly active anti-retroviral therapy (HAART). This is a regimen of combinations of drugs that act on various stages of the HIV life cycle and prevent it from replicating (but it does not prevent expansion or persistence of an existing reservoir). It works very well in adults who are HIV+ and it can successfully get people with high viral loads down to undetectable levels within a few months of starting therapy. The barriers to getting an adult on therapy is really just their knowledge of their HIV status and ability and willingness to take the medications. Anyhow — the infant was on therapeutic doses of HAART from very early in life and very early in the course of the infection; she was followed for about a year with undetectable viral loads and then the hospital lost track of the patient (not uncommon at this site in a non-developed country); after two years, the doctor saw the patient (now 2-3 years old) again and the patient was free of circulating HIV after years without therapy — a functional cure.

These are two very different types of cures and they tell us different and interesting things about the nature of HIV and how good the available therapies are. In the second case, it highlights how important and valuable immediate initiation of therapy is. There is never a good reason to wait. Older recommendations are to initiate therapy after CD4 count has decreased below 400, however, current CDC recommendations are to immediately initiate therapy with some specific recommended regimens. In the case report, the infant’s immune system was probably undeveloped with few latently infected cells. Early in life, our immune systems are undeveloped and the cells undergo high turnover and aren’t as long-lived as adults’ immune cells (which can live for decades, and this is why we need booster vaccines like for tetanus); so in the infant’s case, probably any latently infected cells died during the nature course of development and the HAART prevented any new cells from being infected and her immune system eventually killed off any circulating viral particles to the point that even if one or two latently infected cells remained, her body is able to quickly stop re-emergence of infection.

The other case is more complicated and raises more questions than it answers. First — it is in the “dogma” that all body tissues can be a reservoir for HIV, particularly the brain … and even in the brain some glia can be infected. If this were the case than the Berlin patient would not have experienced the “cure” that he did. Indeed — there are funding opportunity announcements by the National Institutes of Health that operate under the assumption that the brain is a reservoir for HIV. However, this should be controversial because the only papers that showed the presence of HIV (DNA, RNA, and proteins) were in cases from the pre-HAART era, with uncontrolled virus, high viral loads, opportunistic infections, and in severely immunodeficient individuals. The fact is that there isn’t  evidence that there is HIV in the brains of individuals on effective HAART with controlled infections. So the whole premise of some of these research programs is questionable.

Because of these highly publicized cases, there is a push now by funding agencies for research on cure-related research for HIV. Which had previously been abandoned. One avenue that some researchers think is promising is the idea of using chemicals to intentionally re-activate latent virus in HAART-treated patients. The idea is that if HIV were re-activated, the HAART circulating in their bodies would stop any spread, but the re-activation event would promote cell-death, leading to eradication of the reservoir. This is (obviously) risky. Here’s a review of this and some of the other strategies, too.

The problem here is that you wouldn’t know whether it worked until at some point HAART were withdrawn and the virus remained undetected. But if it did not work, then you just exposed the patient to a huge risk of having developed drug-resistance mutations and there’s no guarantee that resuming HAART would be able to control the infection, in fact, there’s significant evidence to the contrary. Secondly, HIV can spread from cell-to-cell via direct contact of “viral synapses” without viral particles being released extracellularly. So in my (I guess conservative) opinion eradication through activation is risky beyond the “first do no harm” principle.

However, there is a clinical trial to assess just such a thing by using histone-deacetylase (HDAC) inhibitors. I don’t think they plan to take the patients off of HAART at any point, so there’s no way of knowing whether it worked as a cure.

I think a cure is going to have to come from a totally novel paradigm which researchers haven’t thought of yet. Probably using some targeted technique where only certain cells will be susceptible to receiving the therapy (like only certain cells are susceptible to infection); and then using some sort of chemical “switch” or “circuit” using DNA — so that when HIV DNA is detected … a switch is turned on which leads to cell death.

In the meantime

Along the way we can learn from the case of the functionally cured infant and do at least three things that I think would be great public health advancements.

  1. Pre-Exposure Prophylactic antiretrovirals (ARV) for at-risk individuals. We’re not going to eliminate risky behaviors in young, sexually active people through Puritanical preaching. Accidents happen, mistakes are made, I think people of a certain age should be given the option to take ARVs prophylactically for a certain amount of time to reduce the risk of acquiring HIV. The only reason not to is cost. Women and men get tubal ligations & vascectomies, and women take birth control; I don’t see anything wrong with pre-exposure prophylaxis (PREP, I think they call it).
  2. Immediate initiation of therapy. The earlier therapy is started, the better the long-term prognosis. For this to happen, the public needs frequent testing and quick and easy access to care.
  3. The last thing is to develop quick and cheap tests for resistance mutations. The genotyping assays currently approved for clinical use can take weeks. Many of these mutations are known and high-throughput sequencing of viral RNA from a newly identified patient could determine within a work-day whether a patient carries a drug resistant virus. This should be routine at the time of diagnosis. As far as I’m aware, there aren’t diagnostic assays like this approved for clinical use yet but a company could easily develop it.
The functionally cured infant case was presented at the 2013 Conference on Retroviruses and Opportunistic Infections in Atlanta by Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Chun T-W.; however the CROI website is down and I can’t find any peer-reviewed case reports. So all we have to go by now are press-releases and second-hand stories. Not terribly encouraging.
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