By Paula Cevaal
To quote the world renowned HIV treatment specialist and researcher Prof. Paul Volberding: “We’ve made a lot of progress. But I don’t talk to any patient who wouldn’t rather be cured than take one pill once a day. So we still have lots of work to do.”1 With the year 2020 fast approaching, we are close to the 50-year mark since HIV was first described. Several big institutions and organizations have announced their goals for an HIV cure to be developed by 2020. How close are we to this goal, and what are the current strategies explored by researchers to achieve a cure?
The curious case of Timothy Brown
The one strategy that has proven successful was the peculiar strategy used in case of Timothy Brown (‘The Berlin Patient’). After controlling his HIV for many years on effective ART, Brown was diagnosed with leukemia for which he required a stem cell transplantation. His oncologist found him a stem cell donor with a specific mutation called CCR5Δ32, which made Brown resistant to HIV. Unfortunately, doctors have not been able to replicate the procedure, indicating scientists still don’t fully understand how Brown was cured. Furthermore, a stem cell transplantation is an expensive and high-risk intervention that is not suitable for all PLHIV.
Defining ‘cure’
Referring back to Volberding’s quote, a cure for HIV is generally defined as the medical procedure that will allow PLHIV to stop their ART without the risk of a viral rebound. Amongst HIV Cure researchers however, the definition of a ‘cure’ is still being discussed and multiple sub-definitions are being used. What researchers call a ‘sterilizing cure’ is the intervention that would completely eradicate the virus from the human body. As explained in ‘HIV Latency: hurdles to a Cure’, HIV resides in the latent reservoir, and thus this sterilizing cure requires a complete eradication of the latent reservoir. On the other hand, a ‘functional cure’ describes an intervention that would permanently prevent the latent reservoir from rebounding, thereby allowing PLHIV to stop their ART even if HIV remains in the body indefinitely.
Sterilizing cure
One of the main strategies to a sterilizing cure is called “Shock and Kill” 2, 3. The (still experimental) intervention consists of a cocktail of drugs (called ‘latency reversing agents’) that ‘shock’ HIV in the latent reservoir out of hiding. By reversing latency, these drugs induce active production of viral particles. Basically, this is a drug-induced viral rebound. This may sound scary, but this drug-induced reactivation of the virus will be combined with ongoing ART, which ensures that the production of new viral particles doesn’t do any harm. Meanwhile though, by producing new viral particles, these ‘shocked’ cells either die immediately or become recognizable which allows for them to be killed. This ‘Shock and Kill’ strategy is being researched extensively and has shown potential, but researchers are struggling to reach the entire latent reservoir with their ‘shock’.
A second and far more experimental strategy involves gene therapy. In ‘The Life Cycle of HIV’, it was explained that HIV integrates into the human DNA and replicates from there. Recently, several techniques have been discovered that can make changes in the DNA at very specific sites. Theoretically, this method (called ‘CRISPR’) is able to cut out the HIV entirely, thereby undoing the infection. At this moment, gene therapy is being studied widely in laboratories, but implementation in clinics is still very much of a future perspective. This is mainly due to the ethical and religious concerns that are being raised in relation to gene therapy in general.
Although achieving a sterilizing cure would be the ideal scenario, it is debatable whether this is remotely possible. To eradicate the latent reservoir and safely stop ART, it is essential to ensure that not even a single latent cell is still present in the body - something which is very difficult to test.
Functional cure
A functional cure (in which the HIV remains in the body indefinitely), may thus be more realistic. One of the strategies studied widely is called immunotherapy. The rationale behind immunotherapies is to boost the body’s own immune system to fight HIV better. This strategy includes the development of an HIV vaccine as well as the development of a sort of antiserum (called ‘broadly neutralizing antibodies’)4. The goal of this strategy is to equip the immune system as such that it can independently eradicate the reservoir without needing ART. There is much overlap between this field of research and cancer research, in which immunotherapy is already used in the clinic. For HIV however, the research is still at an early stage.
The last strategy that should be discussed is another highly experimental one - meaning that it is unlikely to be applicable in the clinics within a few years, but that it is theoretically a very interesting approach. The so called ‘Lock and Block’ strategy embraces the existence of the latent reservoir, and instead of trying to eradicate it, it aims to permanently silence the HIV. This can be done through certain inhibitor drugs or through putting a genetic break on the HIV DNA, ensuring that the latent reservoir can never again reactivate.
All in all, it is fair to say that curing HIV is an ambitious but feasible goal. It will require multidisciplinary teams and long-term commitment from academia, pharmaceutical companies, governments and communities5.
1 https://betablog.org/ucsf-researchers-get-20-million-for-shock-and-kill-hiv-cure-by-2020/
2 Deeks, S. G. HIV: Shock and kill. Nature 487, 439–440 (2012).
3 Rasmussen, T. A. & Lewin, S. R. Shocking HIV out of hiding. Curr. Opin. HIV AIDS 11, 394–401 (2016).
4 Pegu, A., Hessell, A.J., Mascola, J.R., Haigwood, N.L. Use of broadly neutralizing antibodies for HIV-1 prevention. Immunol Rev. (2017)
5 Pitman, M.C., Lau, J.S.Y., McMahon, J.H., Lewin, S.R. Barriers and strategies to achieve a cure for HIV. Lancet HIV. (2018)