Exploring hypoxia and purinergic signaling in HIV persistence

• Applicant: Dr. Roland Schwarzer
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533483360

Despite decades of extensive research and the availability of highly effective antiretroviral medication, the human immunodeficiency virus (HIV) remains a grave public health threat and a leading cause of death globally, The key obstacle to cure HIV are latent reservoirs, which harbor replication competent proviral DNA and are able to reinvigorate spreading infections, even after years of successful antiretroviral therapy (ART). A deeper understanding of HIV latency is urgently needed in order to someday be able to neutralize reservoirs and to end the HIV pandemic for good. As of now it is still not fully understood how latent reservoirs are initially established and how they persist in the face of years of successful ART. The current canonical model states that HIV initially establishes productive infections in highly permissive, fully activated CD4 T cells. Latent reservoirs then manifest in the small fraction of such cells that revert back to a quiescent state, since they are long-lived and devoid of the gene expression landscape to further support viral replication. However, increasing evidence suggests that other factors may be at play or even dominate the formation of latent reservoirs. We have recently discovered that HIV latently-infected cells exhibit an increased expression of the ectonucleotidase CD73 when compared to uninfected or productively infected cells. Importantly, CD73 is involved in production of the highly immunosuppressive adenosine (ADO). Moreover, its expression is controlled by hypoxia, in that low oxygen conditions cause upregulation of CD73. Based on these previous findings we developed the hypoxia-CD73-adenosine (HCA) model of latency that describes HIV persistence as a process that is at least partly controlled by the HCA regulatory axis. Goal of this project is to further investigate the HCA model of latency and explore its translational prospects. In particular, we will utilize CRISPR-based methods to up- or downregulate specific factors involved in HCA signaling and control, thus dissecting how HIV transcription is affected by key HCA proteins. Moreover, we will investigate whether correlations exist in vivo between the expression levels of HCA factors and HIV persistence in blood samples from people living with HIV (PLWH). Finally, we will test whether pharmacological modulators of the HCA axis have the potential to be used as HIV cure drugs, given that they affect HIV transcription and replication. Upon completion, our study will significantly add to our understanding of HIV persistence and the role of HCA in HIV latency establishment and maintenance. Our findings may also inform the design of novel diagnostic tools and therapeutic approaches, thus ultimately contributing to the development of a cure for HIV.

• DFG Programme: Research Grants