Despite decades of rigorous research and the availability of highly effective antiretroviral drugs, HIV remains a grave public health threat and a leading cause of death globally. The key obstacle to a cure for HIV are latent reservoirs, which harbor replication competent proviral DNA and are able to reinvigorate spreading infections, even after years of successful antiviral therapy. Better means of identifying and neutralizing latently infected cells are urgently needed in order to someday be able to achieve remission in individual patients and end the HIV pandemic for good.

Our laboratory seeks to comprehensively characterize latent reservoirs using systems approaches, such as RNA sequencing, mass spectrometry and other high dimensional methods. Goal of this approach is to identify unique features and specific properties of latently infected cells, which could be exploited for both, diagnostic and therapeutic purposes. We then utilize CRISPR interference and activation (CRISPRi/a) to manipulate the cellular factors and pathways identified in our initial screens and pinpoint their role in HIV infections. This strategy will help us to understand the mechanisms that govern viral latency and long-term survival of HIV reservoirs. Ultimately, we strive to validate our findings in specimen from people living with HIV. Here, we will evaluate whether our hits may serve as reservoir markers, diagnostic predictors, or therapeutic targets.

Currently, we are investigating the ectonucleotidase CD73 that was recently discovered using high-dimensional analysis of latently infected cells. CD73 is induced by hypoxia and involved in the enzymatic conversion of the immune stimulating ATP into anti-inflammatory adenosine, which suggests an intriguing mechanism that may contribute to the preferential enrichment of HIV latently infected cells in tissue sanctuaries. Our experiments indicate that hypoxia suppresses HIV transcription, whereas CD73 knockdown promotes viral reactivation from latency, a finding that supports the notion that a direct causality may exist between hypoxia, CD73 expression and HIV replication. Additional experiments will further dissect this pathway and fully unravel if and how its activity impacts HIV transcription

Ein Vortrag von Dr. Roland Schwarzer (Universität Duisburg-Essen)

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