Identification of immunovirological factors that determine an extremely low viral reservoirapproaching the cure of HIV-1 infection

Zusammenfassung

Nearly 40 million individuals are currently living with the human immunodeficiency virus type 1 (HIV-1) worldwide and more than 30 million deaths can be attributed to HIV-1 since the start of the epidemic. The development of combination antiretroviral therapy (cART) was one of the major medical success of the 20th century as it effectively suppresses plasma viremia, improves the immune system function, reduces mortality and morbidity, and the risk of viral transmission. However, cART cannot cure the infection due to the presence of latently infected cells. The number of latently infected cells present in the body, known as the reservoir, varies notably among different HIV-1-infected individuals. Low levels of reservoirs are traditionally related to HIV-1 control or good disease prognosis, but the specific factors provoking a reduction of this reservoir are still unknown. In this context, the aim of this thesis is to characterize the clinical, viral and immunogenetic factors associated with the reduction of the HIV-1 reservoir in three different models: [1] a natural long-term control of the infection (Exceptional Elite controllers or EEC), [2] a natural low HIV-1 reservoir despite regular HIV-1 progression (Low Viral Reservoir Treated individuals or LoViReT), and [3] an induced low reservoir after allogeneic hematopoietic stem cell transplant (allo-HSCT) in persons living with HIV-1. Our results showed that the low-level reservoirs observed in EEC were due to a combination of defective non-evolving virus with protective host genetic factors together with potent HIV-1 specific immune responses. Altogether, the combination of those factors seems important to control HIV-1 replication and reach a spontaneous functional cure. On the other hand, LoViReT individuals seem to have an impaired HIV-1 reservoir establishment since the low levels of reservoir were observed in blood (even before the initiation of treatment) and anatomical sanctuaries. This was supported by a skewed distribution of the provirus among the different CD4+ T cells subpopulations towards short-live subpopulations. However, although LoViReT individuals have a preserved general immune system, they do not have HIV-1 specific immune responses and therefore are not able to control HIV-1 replication in the absence of cART. Finally, the study of HIV-1-infected individuals that received an allo-HSCT showed a remarkably decline of the HIV-1 reservoir in peripheral blood and anatomical compartments, even in the setting of CCR5 wild-type cells. This was most likely due to a potent graft versus HIV-1 effect caused by specific factors of the transplant as a rapid engraftment, an adult donor, or a graft versus host disease. Unfortunately, the lack of a potent HIV-1 specific immune responses sustained in time would result in viral rebound, as observed in one of the studied individuals transplanted with CCR5 wild-type cells. Altogether, we showed that factors related to an impaired viral function will be important to the reduction of HIV-1 reservoir. A combination with a potent HIV-1 specific immune response will be necessary to control the HIV-1 replication in the absence of cART as happened in EEC. Future clinical trials in individuals with a low HIV-1 reservoir, like LoViReT or allo-HSCT individuals, would be of great interest in strategies aimed at boosting HIV-1 immune specific responses with the ultimate goal of curing HIV-1.