The Per-1 Short Isoform Inhibits de novo HIV-1 Transcription in Resting CD4+ T-cells

Author(s): Li Zhao, Mei Liu, Jiayue Ouyang, Zheming Zhu, Wenqing Geng, Jinxiu Dong, Ying Xiong, Shumei Wang, Xiaowei Zhang, Ying Qiao, Haibo Ding, Hong Sun, Guoxin Liang*, Hong Shang*, Xiaoxu Han*

Journal Name: Current HIV Research

Volume 16 , Issue 6 , 2018

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Graphical Abstract:


Background: Understanding of the restriction of HIV-1 transcription in resting CD4+ Tcells is critical to find a cure for AIDS. Although many negative factors causing HIV-1 transcription blockage in resting CD4+ T-cells have been found, there are still unknown mechanisms to explore.

Objective: To explore the mechanism for the suppression of de novo HIV-1 transcription in resting CD4+ T-cells.

Methods: In this study, a short isoform of Per-1 expression plasmid was transfected into 293T cells with or without Tat's presence to identify Per-1 as a negative regulator for HIV-1 transcription. Silencing of Per-1 was conducted in resting CD4+ T-cells or monocyte-derived macrophages (MDMs) to evaluate the antiviral activity of Per-1. Additionally, we analyzed the correlation between Per-1 expression and viral loads in vivo, and silenced Per-1 by siRNA technology to investigate the potential anti-HIV-1 roles of Per-1 in vivo in untreated HIV-1-infected individuals.

Results: We found that short isoform Per-1 can restrict HIV-1 replication and Tat ameliorates this inhibitory effect. Silencing of Per-1 could upregulate HIV-1 transcription both in resting CD4+ Tcells and MDMs. Moreover, Per-1 expression is inversely correlated with viral loads in Rapid progressors (RPs) in vivo.

Conclusion: These data together suggest that Per-1 is a novel negative regulator of HIV-1 transcription. This restrictive activity of Per-1 to HIV-1 replication may contribute to HIV-1 latency in resting CD4+ T-cells.

Keywords: HIV-1, resting CD4+ T-cells, Tat, LTR, viral load, RPs, LTNPs.

Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with aids and at risk for AIDS. Science 1984; 224(4648): 500-3.
Schupbach J, Popovic M, Gilden RV, Gonda MA, Sarngadharan MG, Gallo RC. Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS. Science 1984; 224(4648): 503-5.
Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J 1997; 16(15): 4531-9.
Gallay P, Hope T, Chin D, Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc Natl Acad Sci USA 1997; 94(18): 9825-30.
Bukrinsky MI, Haggerty S, Dempsey MP, et al. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 1993; 365(6447): 666-9.
Freed EO, Martin MA. HIV-1 infection of non-dividing cells. Nature 1994; 369(6476): 107-8.
Fuda N, Ardehali M, Lis J. Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 2009; 461(7261): 186-92.
Lucic B, Lusic M. Connecting HIV-1 integration and transcription: a step toward new treatments. FEBS Lett 2016; 590(13): 1927-39.
Craigie R, Bushman FD. HIV DNA integration. Cold Spring Harb Perspect Med 2012; 2(7): a006890.
Bushman FD, Fujiwara T, Craigie R. Retroviral DNA integration directed by HIV integration protein in vitro. Science 1990; 249(4976): 1555-8.
Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell 2006; 23(3): 297-305.
Ott M, Geyer M, Zhou Q. The control of HIV transcription: keeping RNA polymerase II on track. Cell Host Microbe 2011; 10(5): 426-35.
Wei P, Garber M, Fang S, Fischer W, Jones K. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 1998; 92(4): 451-62.
Kao S, Calman A, Luciw P, Peterlin B. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987; 330(6147): 489-93.
Zhu Y, Pe’ery T, Peng J, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev 1997; 11(20): 2622-32.
Jones K. Taking a new TAK on tat transactivation. Genes Dev 1997; 11(20): 2593-699.
Kao S, Calman A, Luciw P, Peterlin B. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987; 330(6147): 489-93.
Agosto L, Yu J, Dai J, Kaletsky R, Monie D, O’Doherty U. HIV-1 integrates into resting CD4+ T cells even at low inoculums as demonstrated with an improved assay for HIV-1 integration. Virology 2007; 368(1): 60-72.
Maldarelli F. The role of HIV integration in viral persistence: no more whistling past the proviral graveyard. J Clin Invest 2016; 126(2): 438-47.
Pace M, Graf E, Agosto L, et al. Directly infected resting CD4+T cells can produce HIV gag without spreading infection in a model of HIV latency. PLoS Pathog 2012; 8(7): e1002818.
Pan X, Baldauf HM, Keppler OT, Fackler OT. Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. Cell Res 2013; 23(7): 876-85.
Jordan A, Defechereux P, Verdin E. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J 2001; 20(7): 1726-38.
Schröder A, Shinn P, Chen H, Berry C, Ecker J, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110(4): 521-9.
Weinberger L, Dar R, Simpson M. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet 2008; 40(4): 466-70.
Burnett J, Miller-Jensen K, Shah P, Arkin A, Schaffer D. Control of stochastic gene expression by host factors at the HIV promoter. PLoS Pathog 2009; 5(1): e1000260.
Mbonye U, Karn J. Control of HIV latency by epigenetic and non-epigenetic mechanisms. Curr HIV Res 2011; 9(8): 554-67.
Mahmoudi T. The BAF complex and HIV latency. Transcription 2012; 3(4): 171-6.
Ganesh L, Burstein E, Guha-Niyogi A, et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 2003; 426(6968): 853-7.
Coull J, Romerio F, Sun J, et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol 2000; 74(15): 6790-9.
Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999; 340(21): 1614-22.
Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci USA 2009; 106(23): 9403-8.
Martinez-Picado J, Deeks S. Persistent HIV-1 replication during antiretroviral therapy. Curr Opin HIV AIDS 2016; 11(4): 417-23.
Chun T, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano R. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1995; 1(12): 1284-90.
Chun T, Justement J, Lempicki R, et al. Gene expression and viral prodution in latently infected, resting CD4+ T cells in viremic versus aviremic HIV-infected individuals. Proc Natl Acad Sci USA 2003; 100(4): 1908-13.
Romani B, Allahbakhshi E. Underlying mechanisms of HIV-1 latency. Virus Genes 2017; 53(3): 329-39.
Datta PK, Kaminski R, Hu W, et al. HIV-1 Latency and Eradication: Past, Present and Future. Curr HIV Res 2016; 14(5): 431-41.
Khan S, Iqbal M, Tariq M, Baig SM, Abbas W. Epigenetic regulation of HIV-1 latency: focus on polycomb group (PcG) proteins. Clin Epigenetics 2018; 10: 14.
Ruelas D, Greene W. An integrated overview of HIV-1 latency. Cell 2013; 155(3): 519-29.
Caba M, González-Mariscal G, Meza E. Circadian rhythms and clock genes in reproduction: Insights from behavior and the female Rabbit’s brain. Front Endocrinol 2018; 15(9): 106.
Gekakis N, Staknis D, Nguyen H, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998; 280(5369): 1564-6.
Bae K, Jin X, Maywood E, Hastings M, Reppert S, Weaver D. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 2001; 30(2): 525-36.
Cadenas C. van de SL, Edlund K, et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle 2014; 13(20): 3282-91.
Mazzoccoli G, Panza A, Valvano MR, et al. Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients. Chronobiol Int 2011; 28(10): 841-51.
Relles D, Sendecki J, Chipitsyna G, Hyslop T, Yeo CJ, Arafat HA. Circadian gene expression and clinicopathologic correlates in pancreatic cancer. J Gastrointest Surg 2013; 17(3): 443-50.
Hu ML, Yeh KT, Lin PM, et al. Deregulated expression of circadian clock genes in gastric cancer. BMC Gastroenterol 2014; 14: 67.
Mazzoccoli G, Piepoli A, Carella M, et al. Altered expression of the clock gene machinery in kidney cancer patients. Biomed Pharmacother 2012; 66(3): 175-9.
Liu B, Xu K, Jiang Y, Li X. Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non-small cell lung cancer. Int J Clin Exp Pathol 2014; 7(11): 7863-71.
Cao Q, Gery S, Dashti A, et al. A role for the clock gene per1 in prostate cancer. Cancer Res 2009; 69(19): 7619-25.
Mu X, Fu Y, Zhu Y, et al. HIV-1 Exploits the Host Factor RuvB-like 2 to Balance Viral Protein Expression. Cell Host Microbe 2015; 18(2): 233-42.
Baldauf HM, Pan X, Erikson E, et al. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med 2012; 18(11): 1682-7.
Laguette N, Sobhian B, Casartelli N, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 2011; 474(7353): 654-7.
Jáuregui P, Logue E, Schultz M, Fung S, Landau N. Degradation of SAMHD1 by Vpx Is Independent of Uncoating. J Virol 2015; 89(10): 5701-6713.
Friedrich B, Li G, Dziuba N, Ferguson MR. Quantitative PCR used to assess HIV-1 integration and 2-LTR circle formation in human macrophages, peripheral blood lymphocytes and a CD4+ cell line. Virol J 2010; 7: 354.
Butler SL, Hansen MS, Bushman FD. A quantitative assay for HIV DNA integration in vivo. Nat Med 2001; 7(5): 631-4.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 2013; 14(4): R36.
Trapnell C, Williams BA, Pertea G, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010; 28(5): 511-5.
Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol 2013; 31(1): 46-53.
Trapnell C, Roberts A, Goff L, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012; 7(3): 562-78.
Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol 2011; 29(1): 24-6.
Lucifora J, Xia Y, Reisinger F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014; 343(6176): 1221-8.
Gamaldo C, Spira A, Hock R, et al. Sleep, function and HIV: a multi-method assessment. AIDS Behav 2013; 17(8): 2808-15.
White J, Darko D, Brown S, et al. Early central nervous system response to HIV infection: sleep distortion and cognitive-motor decrements. AIDS 1995; 9(9): 1043.
Wang T, Jiang Z, Hou W, et al. HIV Tat protein affects circadian rhythmicity by interfering with the circadian system. HIV Med 2014; 15(9): 565-70.
Nirvani M, Khuu C, Utheim T, Sand L, Sehic A. Circadian clock and oral cancer. Mol Clin Oncol 2018; 8(2): 219-26.
Fu L, Pelicano H, Liu J, Huang P, Lee C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 2002; 111(1): 41-50.
Hunt T, Sassone-Corsi P. Riding tandem: circadian clocks and the cell cycle. Cell 2007; 129(3): 461-4.
Garcia-Fernandez JM, Alvarez-Lopez C, Cernuda-Cernuda R. Cytoplasmic localization of mPER1 clock protein isoforms in the mouse retina. Neurosci Lett 2007; 419(1): 55-8.
Blazek D, Peterlin BM. Tat-SIRT1 tango. Mol Cell 2008; 29(5): 539-40.
Sadaie M, Benter T, Wong-Staal F. Site-directed mutagenesis of two trans-regulatory genes (tat-III,trs) of HIV-1. Science 1988; 239(4842): 910-3.
Zhang Z, Xu J, Fu Y, et al. Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression. Clin Chem 2013; 59(8): 1175-86.
Wang R, Zhang X, Ding H, et al. AID recruits the RNA exosome to degrade HIV-1 nascent transcripts through interaction with the Tat-P-TEFb-TAR RNP complex. FEBS Lett 2018; 592(2): 294.

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Article Details

Year: 2018
Published on: 26 March, 2019
Page: [384 - 395]
Pages: 12
DOI: 10.2174/1570162X17666190218145048

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