By Paula Cevaal
Since its emergence in the ‘80s, only one person in the world has ever been cured of HIV. Just over ten years ago, Timothy Ray Brown (often referred to as ‘The Berlin Patient’) received a stem cell transplant of a healthy donor that was naturally resistant to HIV1. Ever since, Timothy has been an inspiration to scientists as well as other people living with HIV, however it has proven extremely difficult and risky to repeat his procedure. The two upcoming articles will explain why in ten years of advancing science, a cure has not been found, as well as discuss the current strategies that are being explored to change that.
Effective ART is not a cure
As explained in the previous article on Retroviruses, HIV upon infection integrates in to the host cell (human) DNA. The virus subsequently hijacks the host’s cellular machinery to replicate itself. In the article on Treatment of HIV/AIDS it was explained that ART blocks HIV replication by inhibiting the various phases of the HIV life cycle. When taken as prescribed, ART is highly effective in suppressing HIV. However, the regimen is life-long: HIV can rebound after stopping ART2. Why does ART not cure HIV despite being so effective? To understand this, we have to elaborate on the concept of latency.
The latent reservoir
Latency does not only occur in the case of an HIV infection. In fact, in the previous articles on co-infections (here and here) it has been explained that a latent infection is like a dormant infection: the infection is there, but the virus (or bacterium) is not active and thus not causing any symptoms. At a seemingly random moment however, the infection can reactivate and cause disease. In the case of HIV, the exact same happens. Upon infection, part of the infected cells will go into this dormant state where they do harbour the HIV DNA as an integral part of the human DNA, however the virus is not replicating and not causing any harm yet. All these dormant, HIV containing cells together are called ‘the latent reservoir’3,4. Since the HIV residing in this reservoir is not replicating, it will not be affected by ART - after all, ART only inhibits phases of the replication cycle. The latent reservoir is thus a perfect hiding place for HIV where it can remain relatively undetected. As long as effective ART is in place, any reactivation of the latent reservoir will do no harm because ART will immediately block further replication of HIV. However, if someone has, for whatever reason, stopped taking ART and the latent reservoir then reactivates, this person can rebound which can lead to the development of symptoms and AIDS2.
Finding the reservoir
The existence of this latent reservoir thus seems to be the major hurdle to an HIV cure2. But if it is only this specific group of cells that are keeping us away from a cure, why not do surgery and take them out, like with a tumour? Why not do something like chemotherapy to kill all infected cells? Unfortunately, the latent reservoir is spread throughout the entire body and the latent cells are incredibly difficult to distinguish from normal cells. Tumours are often confined and localized and tumour cells are significantly different from healthy cells, which makes them in most cases targetable by drugs like chemotherapy. In contrast, any cell that can be infected with HIV (all CD4+ cells) can become latent, meaning that the latent reservoir includes cells circulating in the entire bloodstream, but also cells in lymph nodes and even the brain4,5,6. Secondly, just like one cannot see from the outside that someone is living with HIV, a latently infected cell cannot be identified as such from the outside as the HIV is hidden inside. Therefore, neither the body’s own immune system nor scientists have found a way to specifically target the latent reservoir without simultaneously damaging healthy cells.
Does this mean that curing HIV is impossible? Many scientists believe otherwise. The next article will discuss the many different strategies that are being explored to prevent, circumvent or eradicate the latent reservoir.
1 Timothy Ray Brown. I Am the Berlin Patient: A Personal Reflection. AIDS Res Hum Retroviruses. 31(1): 2–3 (2015)
2 Deeks, S. G. et al. Towards an HIV cure: a global scientific strategy. Nat. Rev.Immunol. 12, 607–614 (2012).
3 Chun, T.-W. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. 94, 13193–13197 (1997).
4 Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science (80-. ). 278, 1295–1300 (1997).
5 Kumar, N. A. et al. The role of antigen presenting cells in the induction of HIV-1 latency in resting CD4(+) T-cells. Retrovirology 12, 76 (2015).
6 Eriksson, S. et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 9, e1003174 (2013)