Have we cured HIV?

Human immunodeficiency virus (HIV) is a major global public health issue. In 2020, ~680,000 people died from HIV-related causes and a further ~1.5 million people acquired HIV.¹ When left untreated, actively replicating HIV particles target the immune system leading to acquired immunodeficiency syndrome (AIDS). HIV/AIDS results in progressive CD4+ T cell loss, facilitating a wide range of immunological abnormalities and allowing opportunistic infections and cancers to thrive.²

Antiretroviral therapy (ART) has now been available for the treatment of HIV infection for close to two decades, and HIV is now generally considered a chronic condition in which progression to AIDS is increasingly rare. Infected individuals can easily suppress the virus to undetectable levels using ART. However, ART is not a cure for HIV; if an individual were to stop treatment, they would be infective again within weeks.² When considering the cost of ART and its associated toxicity, there is still a need to find a solution to the ever-growing problem of HIV.³

Where disease eradication is the goal, a vaccine is often the weapon of choice. However, a vaccine against HIV, whilst ideal, is not a simple feat. Despite a robust immune response against HIV, infected individuals do not spontaneously eliminate the virus or its detrimental effects, unlike other diseases.² This is because HIV particles can remain hidden within CD4+ cells, where they are masked from the immune system. The infection can continue to spread in this way, and therefore without the production of antibodies against this specific method of CD4+ cell integration, a vaccine against HIV will always fail.²

Although there is no cure, three people have now achieved sustained HIV remission in the absence of ART after undergoing a stem cell transplant from donors carrying a specific CCR5∆32 mutation. This mutation provides natural resistance to the AIDS-causing virus and is very rare, with two copies being found in only ~1% of the general population.⁴

The first patient, Timothy Ray Brown, also known as the "Berlin patient" received a bone marrow transplant to treat his leukaemia and remained free from detectable HIV for over a decade until his death in 2020.5 Next up was Adam Castillejo, the "London patient", who underwent a similar procedure to treat Hodgkin's lymphoma and remains in remission to this day.⁵

This year came reports of the first female, the "New York patient", to have achieved sustained treatment-free HIV remission following a haplo-cord stem cell transplant for treatment of high-risk acute myeloid leukaemia (AML).⁵ At the time of publication, the New York patient had been in HIV remission for 14 months. While this was not unexpected, it was the first time such remission has been seen as a result of a haplo-cord stem cell transplant.⁵ In this procedure, the patient received a partially matched transplant of umbilical cord blood, the donor of which in this case carried the CCR5∆32 genetic mutation. This was then supplemented 24 hours later with adult bone marrow stem cells from a family member.⁵ The adult stem cells divide rapidly, providing a large reserve of cells to compensate for the low cell numbers associated with the cord blood transplant. Using this system, the HIV-resistant cord blood cells will eventually replace the adult stem cells, resulting in the replacement of the HIV-infected CD4+ cells with HIV-resistant counterparts.

It is well known that finding a match for stem cell transplants is very difficult. This challenge is overcome in the case of umbilical cord blood, where it is readily available and only a partial match is required.⁶ The success of this technique increases the potential to treat patients with both HIV and cancer using cord blood, and provides strong evidence for haplo-cord transplants being a successful means of treatment.

While such an invasive high-risk strategy will not be a viable treatment option for generic treatment of HIV, it confirms that curing HIV is possible and further strengthens that gene therapy is a viable strategy in developing an HIV cure moving forwards.

References

1. World Health Organisation. HIV/AIDS factsheet. November 2021. Available at: https://www.who.int/news-room/fact-sheets/detail/hiv-aids (accessed May 2022).
2. Deeks SG, et al. Nat Rev Dis Primers 2015;1:15035.
3. Schackman BR, et al. Med Care 2015;53:293-301.
4. Gomulska M, et al. Folia Med Cracov 2014;54:5-13.
5. Bryson, Y. HIV-1 remission with CCR5∆32∆32 haplo-cord transplant in a US woman: IMPAACT P1107. February 2022. Available at: https://www.impaactnetwork.org/sites/default/files/inline-files/Final%20IMPAACTP1107_FINAL%20CROI%20%20revised%2012Feb2022%20BRYSON%203.pdf (accessed May 2022).
6. Ballen KK, et al. Blood 2013;122:491-498.