Role of lncRNAs in cell activation, actin remodeling and HIV latency in CD4 T lymphocytes

• Applicant: Professor Oliver T. Fackler, Ph.D.
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508136175

Therapeutic reversal of HIV latency (i.e. transcriptional silence) and elimination of the latent reservoir is the final frontier towards a cure of HIV infection. However, current “shock-and kill” or “shock-and-lock” strategies unfortunately fail in clinical settings as they do not reach all anatomical sites of the reservoir and not all proviral HIV genome copies are sensitive to transcriptional activation by current regimens. Since the underlying mechanisms of this insensitivity to latency reversal are unknown, the inability to design effective therapeutic options that control HIV expression reflects gaps in our understanding of how HIV gene expression and viral latency are regulated. The understanding of how Pol II, the host transcription machinery and epigenetic modifications regulate steps of HIV gene expression is as advanced as that for cellular genes. However, the emerging role of lncRNAs as regulators of cellular gene expression has not yet been carefully studied in the context of T cell activation and HIV gene expression, and may be the key gap to a comprehensive understanding of steps that establish viral latency. Our preliminary results suggest that Cytor (lincRNA00152) is a novel activator of HIV gene expression that suppresses viral latency establishment and facilitates latency reversal as well as actin dynamics in CD4 T cells lines. Building on these findings, we now aim at (i) dissecting the mechanisms by which Cytor regulates HIV gene activation and host cell actin dynamics, (ii) exploring potential mechanistic links between these activities and (iii) defining the physiological relevance of Cytor functions in primary cells including cells from HIV patients. In the long-term these efforts aim at achieving a comprehensive understanding of the role of cellular lncRNAs in CD4 T cell activation as well as HIV gene expression and latency establishment and at evaluating host cell lncRNAs as therapeutic target in latency reversal approaches.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Ran Taube