ABSTRACT To successfully eliminate the HIV reservoir, it is critical to understand the molecular events that control HIV latency. While the key roles that host protein factors play in the regulation of HIV transcription and viral latency have been extensively studied, our understanding of how the non-coding transcriptome, especially long non- coding RNA (lncRNA), contribute to viral latency control is limited. To better understand the regulatory roles lncRNAs play in the control of HIV transcription and viral latency, we employed RNA-Seq analysis and compared the transcriptome in activated versus resting HIV-infected cells. We identified numerous lncRNAs that are differentially expressed, therefore are candidates for HIV latency regulation. Among them, one lncRNA, Cytoskeleton Regulator (Cytor), activates HIV transcription and viral latency. Our results also indicate that the depletion of Cytor suppresses latent HIV reactivation by reducing the occupancy of RNA Polymerase II (Pol II) and the levels of histone activation markers on the viral promoter. Additional biochemical and proteomic analyses showed that Cytor occupies the HIV promoter and associates with Positive Transcription Elongation Factor b (P- TEFb), which is an essential cellular factor for transcription elongation of HIV and cellular genes. In light of these findings, we hypothesize that by recruiting P-TEFb to the HIV promoter, Cytor activates HIV gene expression. To test this hypothesis, we will determine whether Cytor directly binds P-TEFb and recruits the cellular transcription elongation complex to the HIV promoter. Additional preliminary RNA-Seq analysis indicated that Cytor depletion results in broad changes in the host transcriptome. We will therefore identify downstream targets of Cytor and determine their indirect effects on HIV gene expression. Significantly, our results will be further confirmed in a clinically relevant context, as we will manipulate Cytor expression in CD4+ primary cells and determine the magnitude of Cytor’s therapeutic potential for HIV reactivation and latency reversal or, alternatively, to latency induction. Our study will provide new insights into the regulation of HIV transcription and viral latency by lncRNAs. Its successful completion will lay the groundwork for the development of new RNA-based therapies that will be added to current therapeutic protocols to eliminate HIV infection and the persistent viral reservoir.