Projektleiter: Prof. Dr. med. Hendrik Streeck
The development of potent antiretroviral treatment (ART) strategies has reatly improved the prognosis for infected individuals with access to care. However, once HIV establishes infection, the virus persists indefinitely as an integrated part of the genome in a small population of latently infected CD4+ T cells. Cure or eradication attempts have so far failed and HIV remains a lifetime economic, psychological and medical burden for infected individuals. One major hurdle impeding more targeted approaches to eradicate remaining HIV or HIV-infected cells is the lack of knowledge regarding the precise cellular and compartmental location of the latent HIV reservoir in antiretroviral therapy (ART)-treated individuals.
To define novel curative therapeutic strategies against HIV it is pivotal to define the barriers that prevent HIV eradication. In particular in the gastrointestinal tract it is currently unknown in which cells and anatomical locations HIV resides even after long-term HAART treatment and whether latently infected cells are protected from immune surveillance. Moreover, it is unknown whether CD8 T cells in the gastrointestinal tract generally have the capabilities to recognize and kill virally infected cells and whether overcoming anatomical barriers may yield in reduction of the viral reservoir. To understand and define the barriers that currently prevent eradication of HIV we plan in collaboration with Dr. Stefan Esser to prospectively obtain gastrointestinal biopsies of HIV+ HAART treated and untreated individuals. We will use novel technologies such as index-cell sorting and Fluidigm gene chip analysis to define the cellular latent reservoir in the gastrointestinal tract. We will determine whether immune privileged sites in the gastrointestinal tract prevents CD8 T cells from recognizing and killing latently infected cells and we will address whether destruction of these immune privileged sites will allow CD8 T cells to access latently infected cells and reduce the viral reservoir. Specifically we propose the following specific aims:
1) to determine sites of HIV persistence in the gastrointestinal tract in treated and untreated HIV infected individuals; 2) to assess the ability of CD8 T cells to recognize and kill HIV infected cells in the gastrointestinal tract in comparison to the periphery and 3) to define barriers to CD8 T cell mediated recognition in the gastrointestinal tract and test potential therapeutic strategies to overcome.
Overall, this highly collaborative proposal is designed to define the immunological and anatomical barriers for HIV cure in the gastrointestinal tract and define potential avenues for future therapeutic strategies.