9348–9360 Nucleic Acids Research, 2017, Vol. 45, No. 16 Published online 20 June 2017 doi: 10.1093/nar/gkx550 Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency Zheng Zhang1,†, Bryan C. Nikolai1,†, Leah A. Gates1, Sung Yun Jung2, Edward B. Siwak3, Bin He1,4, Andrew P. Rice3, Bert W. O’Malley1 and Qin Feng1,*
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA, 2Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA, 3Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA and 4Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX, USA
Received February 06, 2017; Revised May 25, 2017; Editorial Decision June 13, 2017; Accepted June 15, 2017
ABSTRACT INTRODUCTION In eukaryotic cells, the gene expression status Human immunodeficiency virus (HIV) is a retrovirus that is strictly controlled by epigenetic modifications causes acquired immunodeficiency syndrome. HIV infec- on chromatin. The repressive status of chromatin tion of CD4+ helper T lymphocytes is a multistep process, largely contributes to HIV latency. Studies have involving fusion and entry through interaction with CD4 re- shown that modification of histone H3K27 acts as ceptor and CCR5 co-receptor, reverse transcription of HIV viral RNA into double-stranded viral DNA, and integra- a key molecular switch for activation or suppression tion of viral DNA into the host cell genome. Combination of many cellular genes. In this study, we found that Antiretroviral Therapy (cART), also known as highly ac- K27-acetylated histone H3 specifically recruited Su- tive antiretroviral therapy (HAART), employs the use of per Elongation Complex (SEC), the transcriptional three or more antiretroviral drugs to inhibit the key steps of elongation complex essential for HIV-1 long terminal HIV infection, and has been very effective in HIV-infected repeat (LTR)-mediated and general cellular transcrip- patients by suppressing HIV replication and maintaining tion. Interestingly, H3K27 acetylation further stim- the virus at undetectable levels. However, although continu- ulates H3R26 methylation, which subsequently ab- ous cART is life-prolonging, it never eradicates HIV infec- rogates the recruitment of SEC, forming a negative tion or cures this disease. Interruption of treatment quickly feedback regulatory loop. Importantly, by inhibiting results in virus replication and recurrence of the disease methyltransferase activity of CARM1, the enzyme re- (1). Therefore, HIV-infected patients must receive lifelong cART treatment, which presents economic and therapeutic sponsible for H3R26 methylation, HIV-1 transcription burdens. is reactivated in several HIV latency cell models, in- The principal impediment to eradication of HIV infec- cluding a primary resting CD4+ T cell model. When tion is the latent reservoir of HIV provirus. HIV provirus combined with other latency disrupting compounds persists in multiple tissues and cells, particularly the long- such as JQ1 or vorinostat/SAHA, the CARM1 in- lasting, resting CD4+ T cells. Reversing proviral latency is hibitor achieved synergistic effects on HIV-1 activa- believed to be a major challenge for strategies to eradicate tion. This study suggests that coordinated and dy- HIV from an individual and achieve a functional cure. To namic modifications at histone H3K27 and H3R26 or- this end, recently discussed and tested approaches to tar- chestrate HIV-1 LTR-mediated transcription, and po- get latency involve ‘shock and kill’ strategies, which pro- tentially opens a new avenue to disrupt latent HIV-1 pose to reactivate (‘shock’) latent HIV in the presence of infection by targeting specific epigenetic enzymes. cART and apply immune-based therapy to purge (‘kill’) these reservoirs (2,3). Mechanistically, epigenetic transcrip- tional processes drive HIV latency in T cells, as the repres- sive status of chromatin largely contributes to HIV latency (4). In order to reactivate the latent virus, it is essential to
*To whom correspondence should be addressed. Tel: +1 713 798 6247; Fax: +1 713 790 1275; Email: [email protected] †These authors contributed equally to this work as first authors. Present address: Zheng Zhang, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.