Despite the crucial clinical importance of HIV latency and reactivation, our knowledge of the mechanisms involved in establishment of latency and the subsequent reactivation is very incomplete. In this application we will examine the role of non-coding RNAs, both miRNA and lncRNA, on the control of HIV transcription and establishment of epigenetic silencing of HIV proviruses. Studies in numerous systems have pointed to complex interactions among different chromatin modifying factors and the extensive involvement of lncRNAs and miRNA in regulation of locus-specific epigenetic changes. While it is likely that similar RNA-protein networks govern the epigenetic changes and thus latency and reactivation of HIV proviral population, the specific mechanisms and RNAs have yet to be identified. We will test the hypothesis that the establishment, maintenance and exit from the latent state is governed by epigenetic changes imposed by chromatin modifying complexes which are guided to the proviral locus through association with one or more lncRNAs and miRNAs. This work will take advantage of a novel ex vivo system developed in the Karn laboratory which enables us to investigate the induction of both latency and reactivation in uniform primary T-effector memory cell populations, extensive experience with lncRNAs in the Valadkhan laboratory and new insights into the role of miRNA and lncRNA in the regulation of HIV Tat and transcription from the Zhang laboratory. The work will focus around the following Specific Aims:
Aim 1 (US). Identification of chromatin modifying factors involved in inducing latency-related epigenetic changes.
Aim 2 (US). To define the role of long non-coding RNAs (lncRNAs) in HIV-related epigenetic changes.
Aim 3 (China): To determine whether miRNAs contribute to HIV-1 latency and to study their mechanisms of action.
Aim 4 (China): To study degradation of Tat protein induced by NRON lncRNA and its contribution to HIV- 1 latency. Successful completion of the four synergistic aims of this application will require the exchange of information and materials between the US and Chinese groups. We will leverage the experience of the US principal investigator, Dr. Jonathan Karn and his colleague Dr. Saba Valadkhan, on molecular studies of HIV latency and the analysis of lncRNA and the complementary expertise of the Chinese principal investigator, Dr. Hui Zhang, on analysis of the function of microRNAs (miRNAs).

Public Health Relevance

This project is in response to RFA-AI-14-057: U.S.-China Program for Research Toward a Cure for HIV/AIDS (R01). It leverages the expertise of US and Chinese laboratories to study the role of non-coding RNA in the regulation of HIV latency, a key molecular step in establishing viral reservoirs that escape drug therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-M (50))
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Stansell, Elizabeth H
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Case Western Reserve University
Schools of Medicine
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Nguyen, Kien; Das, Biswajit; Dobrowolski, Curtis et al. (2017) Multiple Histone Lysine Methyltransferases Are Required for the Establishment and Maintenance of HIV-1 Latency. MBio 8:
Valadkhan, Saba; Gunawardane, Lalith S (2016) lncRNA-mediated regulation of the interferon response. Virus Res 212:127-36
Zhang, Yijun; Yin, Yue; Zhang, Shaoying et al. (2016) HIV-1 Infection-Induced Suppression of the Let-7i/IL-2 Axis Contributes to CD4(+) T Cell Death. Sci Rep 6:25341
Geng, Guannan; Liu, Bingfeng; Chen, Cancan et al. (2016) Development of an Attenuated Tat Protein as a Highly-effective Agent to Specifically Activate HIV-1 Latency. Mol Ther 24:1528-37