Despite the success of antiretroviral therapy (ART) in decreasing mortality for HIV-infected individuals, ART has not cured HIV/AIDS. The failure to eradicate HIV infection during ART stems from the virus’ ability to persist in the body in multiple cell types and tissues. Without lifetime therapy, the virus quickly rebounds resulting in accelerated morbidity and mortality. The most commonly studied form of persistence is in memory CD4+ T-cells (CD4+ Tm-cells) that are harbouring the virus out of view of drugs or from the immune system. However, evidence indicates that other long-lived cells, known as myeloid cells, might contribute to HIV persistence. Cells that allow virus persistence are called viral reservoirs (VRs) and represent the main barrier to an HIV cure. While much is known about HIV persistence, many puzzles remain about the source of persistent HIV, the mechanisms underlying the establishment and persistence of VRs, particularly in CD4+ Tm-cells, and the ways to eliminate VRs. The Canadian HIV Cure Enterprise 2.0 (CanCURE 2.0), a team of leading Canadian HIV researchers, are pursuing an integrated and innovative research program informed by new knowledge in the field and new findings generated under CanCURE 1.0 (2014-2019). This collaborative project combines the efforts of prominent Canadian investigators, as well as two knowledge users who present the perspective of individuals living with HIV. The scientific program is based on three complementary research Themes.
●Theme 1 is aimed to uncover mechanisms by which specific antigens and antigen presenting cells of myeloid lineage lead to the establishment and persistence of VR in CD4+ Tm-cells.
●Theme 2 is aimed to define the direct contribution of long-lived self-renewing tissue-resident myeloid cells to HIV/SIV persistence during ART.
●Theme 3 is aimed to further develop innovative CanCURE 1.0 therapeutic interventions that target the VR in both T-cells and myeloid cells, notably macrophages, and translate new discoveries into therapeutic strategies.
Furthermore, CanCURE 2.0 research Cores support the Team with relevant animal models (Animal Models Core), and clinical platforms (Clinical Core). Interactions between research Theme units and Cores create a multidisciplinary approach driving the science towards our aim of generating effective therapeutic interventions against HIV persistence in individuals under antiretroviral therapy.
The Animal Models Core develops animal models to test therapeutic approaches against persistent HIV viral reservoirs (VR) during antiretroviral therapy (ART). The Team benefits from models in simian immunodeficiency virus (SIV)-infected primates and humanized mice.
Co-Leaders: N. Chomont & T. Murooka
Participants: P. Ancuta, M.J. Tremblay, M. Ostrowski, A. Kumar, E.A. Cohen, K. Fowke, L. Falcone
Collaborator: M. A. Klein
Although the direct contribution of long-lived myeloid cells to HIV persistence during ART remains a subject of open investigation (to be explored in Theme 2), it is well established that HIV primarily persists in antigen-experienced memory CD4+T-cells. In individuals on ART, clonally expanded CD4+T-cells represent at least 50-60% of persistently infected cells harboring replication competent HIV. This suggests that proliferation of these cells, which is driven by the presence of antigens, critically contributes to the maintenance of the viral reservoir (cells that allow virus persistence). The generation and maintenance of memory T-cells require continual cell-to-cell interactions between antigen presenting cells and CD4+T-cells within lymphoid organs. Antigen presenting cells such as dendritic cells and macrophages present antigens in the context of class II major histocompatibility complex molecules, and together with soluble/membrane-bound co-stimulation signals, instruct and support long-term survival of antigen-specific CD4+T-cells. In humans, the establishment of long-term immunological memory, either through natural infection or vaccination, is restricted to unique antigens. Therefore, it is reasonable to assume that HIV reservoirs are also established and maintained in CD4+T-cells with unique antigen specificities. In Theme 1, CanCURE investigators will investigate whether specific antigens have the ability to imprint CD4+T-cells with unique metabolic/transcriptional profiles that can be exploited by the HIV virus to promote viral reservoir establishment and persistence.