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This Spanish study has identified various factors influencing the elimination of the HIV reservoir which may be useful for designing cure strategies

Miguel Vázquez – 10/22/2018

A Spanish study by IrsiCaixa and Gregorio Marañón Hospital published in Annals of Internal Medicine reveals that five HIV-patients present an undetectable HIV reservoir after having received a stem cell transplant to treat a blood disease. In addition, HIV antibodies are not found in one of them. The study has identified which factors may influence the reduction of the viral reservoir, such as, for example, the origin of the stem cells, the time the donor’s cells take to replace those of the patient and the development of the graft-versus-host disease. The authors warn that it is still too early to confirm the success of this cure strategy. This can only be known in another stage of the study, when the antiretroviral treatment is withdrawn from patients. However, researchers point out that these findings might be useful for developing a strategy to cure this infection in the future.

Current antiretroviral treatments allow to control HIV replication by reducing the viral load in the blood to levels called “undetectable.” This results in health benefits for the patient (see La Noticia del Día 24/02/2016) and also for their sexual partners, as it makes the risk of sexual transmission of HIV non-existent under certain circumstances (see La Noticia del Día 16/05/2018).

Nevertheless, the antiretroviral treatment fails to eliminate the infection, as the virus remains in the body in what are called latent viral reservoirs, which are a group of infected cells which continue hosting the virus, but cannot be detected by the immune system or exposed to the action of antiretroviral drugs. Some studies had detected substantial reductions in the HIV-1 latent reservoir after an allogeneic hematopoietic stem cell transplant, including the complete eradication of the HIV-1 in the only confirmed case of HIV cure, known as the Berlin patient (Timothy Brown). This person with HIV needed a bone marrow transplant to treat leukemia, and his doctor decided to use stem cells from a donor who had a mutation (CCR5 delta 32) due to which his CD4 cells did not have a co-recipient the virus needed to enter the body (see El Paciente de Berlín, en Lo+Positivo 50).

It is an extremely risky procedure, so it cannot be performed indiscriminately on all people with HIV. However, it may offer some clues on possible mechanisms to eradicate the infection.

This study had a cohort of people with HIV who had received a bone marrow transplant to treat an hematologic disease. The team of researchers wanted to confirm whether, in addition to such CD4 mutation, there were other factors influencing the cure of the Berlin patient. Therefore, six participants were considered in the analysis. They had survived at least two years after the transplant and their cells did not have the CCR5 Delta 32 mutation.

After the transplant, all participants continued receiving their antiretroviral treatment and achieved remission of their hematologic disease.

After several tests, it was confirmed that the viral reservoir was undetectable in the blood and tissues of five of those six people. Additionally, one of them had a seroreversion, that is, this person did not present an antibody response to HIV after 7 years since the transplant was performed. These data are very encouraging, as they indicate that the infection may have been eliminated, but this still cannot be affirmed for sure, since these people still receive treatment.

The only person who maintained a detectable viral reservoir had received an umbilical cord blood transplant, unlike the other participants, who had received a bone marrow transplant. The donor’s cells took 18 months to replace those of this person, although the expected time is a couple of months or up to one year. The authors of the study confirmed that the speed at which this replacement takes place has an influence on viral reservoir reduction.

Furthermore, the person with detectable reservoir did not suffer from the graft-versus-host disease, unlike the rest of participants. This suggests that this reaction may also play an important role in reservoir elimination. Therefore, controlling this effect so that it is not fatal for the patient might help eradicate HIV from the body.

As mentioned before, this transplant is very dangerous, and its use may not be considered as a generalized cure strategy. However, findings of this study might contribute to the design of cure strategies which replicate reservoir elimination mechanisms, but in a safer way for people.

Previous studies had already shown that allogeneic stem cell transplants achieved significant virus load reductions in the body. Nevertheless, these HIV reductions are not necessarily equivalent to a cure, as there are precedents in which the viral load has rebounded after months and even years after having interrupted treatment (see La Noticia del Día 06/03/2017). For this reason, the authors of this study affirm that the next step will be to conduct a clinical study where some of these people will interrupt their antiretroviral treatment to confirm whether the virus has been eradicated from the body or not.

SourcePress release IrsiCaixa/Prepared by the author (gTt-VIH)

Reference: Salgado M, Kwon M, Gálvez C, et al. Mechanisms that Contribute to a Profound Reduction of the HIV-1 Reservoir after Allogeneic Stem Cell Transplant. Ann Intern Med. 2018. DOI: 10.7326/M18-0759