Current HIV treatments efficiently block viral multiplication but cannot cure infection as they do not target HIV infected cells. HIV cure or profound HIV remission have been described in three persons with HIV who underwent allogeneic stem cell transplantation to treat severe blood cancers. However, this procedure has not eradicated the virus in other persons. A work led by scientists from the University Medical Center Hamburg and the Institut Pasteur in the context of the ICISTEM international consortium has analyzed the evolution of the immune system in 16 persons with HIV after allogeneic stem cell transplantation. The scientists identified a phase of strong activation of the immune system occurring after the transplant which may provide a window of vulnerability for the reseeding of the HIV reservoir in the expanding donor cells. Their findings are published in the journal Science Translational Medicine on May 6, 2020.
The antiretroviral treatment used today is not able to eliminate the virus from the body, which remains nested in immune cells, in particular CD4 cells, from where the virus starts multiplying again and infecting new cells if the antiviral treatment is discontinued. There is currently no strategy that can target and selectively eliminate the infected cells from the organism. Allogeneic stem cell transplant is used to treat patients with life-threatening blood cancers, such as leukemia or lymphoma, or severe disorders of the immune system. During these transplants, most of the immune cells from these patients are eliminated by ablation techniques. Stem cells from a healthy donor are then used to replace damaged bone marrow in the patients in order to restore their immune system. Some persons with HIV also need to undergo allogeneic stem cell transplantion to resolve different types of hematological cancers. Such interventions have been accompanied by spectacular decreases in the number of HIV-infected cells, which became undetectable in almost all cases. Moreover, in three individuals the virus remains undetectable despite interruption of antiretroviral treatment, indicating that HIV cure or at least deep HIV remission has been achieved in these persons. In all three cases, the patients were transplanted with stem cells from donors who carried a mutation (CCR5D32) that impairs the expression on the cell surface of one of the main HIV entry receptors, rendering them resistant to some HIV strains. In contrast, viral replication started again in several other instances in which persons with HIV who had received allogeneic stem transplant discontinued their antiretroviral treatment.
The ICISTEM study (www.icistem.org) compiles exceptional cases of persons with HIV who need allogeneic stem cell transplant. The aim is to perform comprehensive studies on the HIV dynamics, viral reservoir and immune responses after the transplant and identify the factors leading to HIV cure/remission or resurgence in these patients. A study led by scientists from the HIV, inflammation and persistence unit at the Institut Pasteur and from the Infectious Diseases Unit at University Medical Center Hamburg-Eppendorf has analyzed the evolution of the T cell compartment after the transplantation in 16 persons with HIV and antiretroviral treatment, including 5 patients who received cells with the CCR5Δ32 mutation. They found that the initial weeks after the transplantation, when cells from both the donor and the patient still coexisted, were characterized by strong activation of CD4 cells. Therefore, although only a few original cells from the patients remained during this period, their activation may promote the reactivation of HIV provirus and the reseeding of infection in expanding CD4 cells from donors, which are perfect HIV targets if the infection is not avoided by efficient antiretroviral treatments or genetic barriers (such as the CCR5D32 mutation for viruses using such receptor).
The researchers also observed that new CD8 responses directed against HIV proteins developed from donor cells following this period. This indicated that during their expansion the cells from the donors where in contact with HIV factors and were trained to react against them, confirming the existence of a “window of vulnerability” during which infection of cells from donor origin may occur. However, these new CD8 responses against HIV were weak and of poor quality when compared to responses that were developed in the same patients against other chronic infections such as cytomegalovirus, known to reactivate during the transplantation. In some cases, HIV responses persisted at relatively high frequencies for many years after the transplantation, which might reveal HIV persistence in hidden anatomical reservoirs in these individuals, as confirmed in at least one of the cases studied who experienced viral rebound after interruption of antiretroviral treatment.
Together with previous results from the ICISTEM consortium, these novel results reveal a vulnerability that may explain why allogeneic stem cell transplant, despite drastically decreasing the number of infected cells in the organism, may not totally eradicate the virus from the body. A few infected cells may remain unnoticed in non-accessible organs and promote viral rebound that would not be controlled by the relatively inefficient immune responses already present. Additional immunotherapies or interventions aimed to reinforce control may be needed to achieve remission in persons with HIV after allogeneic stem cell transplant who did not receive cells with intrinsic resistance to infection.
This article was first published on 7 May by Institut Pasteur.