Epigenetics, N-myrystoyltransferase-1 and Casein Kinase-2-alpha Modulates the Increased Replication of HIV-1 CRF02_AG, Compared to Subtype-B Viruses

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jul 25

PMID 31337802

Citations 3

Authors

Biju Bhargavan

Georgette D Kanmogne

Affiliations

Soon will be listed here.

Abstract

HIV subtypes distribution varies by geographic regions; this is likely associated with differences in viral fitness but the predictors and underlying mechanisms are unknown. Using in-vitro, in-vivo, and ex-vivo approaches, we found significantly higher transactivation and replication of HIV-1-CRF02_AG (prevalent throughout West-Central Africa), compared to subtype-B. While CRF02_AG-infected animals showed higher viremia, subtype-B-infected animals showed significantly more weight loss, lower CD4+ T-cells and lower CD4/CD8 ratios, suggesting that factors other than viremia contribute to immunosuppression and wasting syndrome in HIV/AIDS. Compared to HIV-1-subtype-B and its Tat proteins(Tat.B), HIV-1-CRF02_AG and Tat.AG significantly increased histone acetyl-transferase activity and promoter histones H3 and H4 acetylation. Silencing N-myrystoyltransferase(NMT)-1 and casein-kinase-(CK)-II-alpha prevented Tat.AG- and HIV-1-CRF02_AG-mediated viral transactivation and replication, but not Tat.B- or HIV-1-subtype-B-mediated effects. Tat.AG and HIV-1-CRF02_AG induced the expression of NMT-1 and CKII-alpha in human monocytes and macrophages, but Tat.B and HIV-1-subtype-B had no effect. These data demonstrate that NMT1, CKII-alpha, histone acetylation and histone acetyl-transferase modulate the increased replication of HIV-1-CRF02_AG. These novel findings demonstrate that HIV genotype influence viral replication and provide insights into the molecular mechanisms of differential HIV-1 replication. These studies underline the importance of considering the influence of viral genotypes in HIV/AIDS epidemiology, replication, and eradication strategies.

Citing Articles

CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice.

Bhargavan B, Woollard S, McMillan J, Kanmogne G Mol Neurodegener. 2021; 16(1):78.

PMID: 34809709 PMC: 8607567. DOI: 10.1186/s13024-021-00500-0.

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections.

Kosciuk T, Lin H ACS Chem Biol. 2020; 15(7):1747-1758.

PMID: 32453941 PMC: 7841852. DOI: 10.1021/acschembio.0c00314.

Attention/Working Memory, Learning and Memory in Adult Cameroonians: Normative Data, Effects of HIV Infection and Viral Genotype.

Kanmogne G, Fonsah J, Umlauf A, Moul J, Doh R, Kengne A J Int Neuropsychol Soc. 2020; 26(6):607-623.

PMID: 32066518 PMC: 8582275. DOI: 10.1017/S1355617720000120.

References

Brennan C, Bodelle P, Coffey R, Devare S, Golden A, Hackett Jr J . The prevalence of diverse HIV-1 strains was stable in Cameroonian blood donors from 1996 to 2004. J Acquir Immune Defic Syndr. 2008; 49(4):432-9. DOI: 10.1097/QAI.0b013e31818a6561. View

Anastassopoulou C, Kostrikis L . Global genetic variation of HIV-1 infection. Curr HIV Res. 2006; 4(3):365-73. DOI: 10.2174/157016206777709456. View

Brown B, Darden J, Tovanabutra S, Oblander T, Frost J, Sanders-Buell E . Biologic and genetic characterization of a panel of 60 human immunodeficiency virus type 1 isolates, representing clades A, B, C, D, CRF01_AE, and CRF02_AG, for the development and assessment of candidate vaccines. J Virol. 2005; 79(10):6089-101. PMC: 1091694. DOI: 10.1128/JVI.79.10.6089-6101.2005. View

Takamune N, Gota K, Misumi S, Tanaka K, Okinaka S, Shoji S . HIV-1 production is specifically associated with human NMT1 long form in human NMT isozymes. Microbes Infect. 2008; 10(2):143-50. DOI: 10.1016/j.micinf.2007.10.015. View

Teto G, Fonsah J, Tagny C, Mbanya D, Nchindap E, Kenmogne L . Molecular and Genetic Characterization of HIV-1 Tat Exon-1 Gene from Cameroon Shows Conserved Tat HLA-Binding Epitopes: Functional Implications. Viruses. 2016; 8(7). PMC: 4974531. DOI: 10.3390/v8070196. View

Gupta S, Mitra D . Human immunodeficiency virus-1 Tat protein: immunological facets of a transcriptional activator. Indian J Biochem Biophys. 2008; 44(5):269-75. View

Woollard S, Bhargavan B, Yu F, Kanmogne G . Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction. J Cereb Blood Flow Metab. 2014; 34(6):1047-59. PMC: 4050250. DOI: 10.1038/jcbfm.2014.54. View

Meggio F, DAgostino D, Ciminale V, Chieco-Bianchi L, Pinna L . Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases. Biochem Biophys Res Commun. 1996; 226(2):547-54. DOI: 10.1006/bbrc.1996.1392. View

Denton P, Garcia J . Humanized mouse models of HIV infection. AIDS Rev. 2011; 13(3):135-48. PMC: 3741405. View

10.

Wright M, Heal W, Mann D, Tate E . Protein myristoylation in health and disease. J Chem Biol. 2009; 3(1):19-35. PMC: 2816741. DOI: 10.1007/s12154-009-0032-8. View

11.

Konings F, Zhong P, Agwara M, Agyingi L, Zekeng L, Achkar J . Protease mutations in HIV-1 non-B strains infecting drug-naive villagers in Cameroon. AIDS Res Hum Retroviruses. 2004; 20(1):105-9. DOI: 10.1089/088922204322749558. View

12.

Bhargavan B, Woollard S, Kanmogne G . Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication. Cell Signal. 2015; 28(2):7-22. PMC: 4890564. DOI: 10.1016/j.cellsig.2015.11.005. View

13.

Willey R, Maldarelli F, Martin M, Strebel K . Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol. 1992; 66(12):7193-200. PMC: 240416. DOI: 10.1128/JVI.66.12.7193-7200.1992. View

14.

Meggio F, Pinna L . One-thousand-and-one substrates of protein kinase CK2?. FASEB J. 2003; 17(3):349-68. DOI: 10.1096/fj.02-0473rev. View

15.

Kaur G, Mehra N . Genetic determinants of HIV-1 infection and progression to AIDS: immune response genes. Tissue Antigens. 2009; 74(5):373-85. DOI: 10.1111/j.1399-0039.2009.01337.x. View

16.

Giang D, Cravatt B . A second mammalian N-myristoyltransferase. J Biol Chem. 1998; 273(12):6595-8. DOI: 10.1074/jbc.273.12.6595. View

17.

Lusic M, Marcello A, Cereseto A, Giacca M . Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter. EMBO J. 2003; 22(24):6550-61. PMC: 291826. DOI: 10.1093/emboj/cdg631. View

18.

Eberle J, Gurtler L . HIV types, groups, subtypes and recombinant forms: errors in replication, selection pressure and quasispecies. Intervirology. 2012; 55(2):79-83. DOI: 10.1159/000331993. View

19.

Mulekar J, Huq E . Expanding roles of protein kinase CK2 in regulating plant growth and development. J Exp Bot. 2013; 65(11):2883-93. DOI: 10.1093/jxb/ert401. View

20.

Meggio F, Marin O, Boschetti M, Sarno S, Pinna L . HIV-1 Rev transactivator: a beta-subunit directed substrate and effector of protein kinase CK2. Mol Cell Biochem. 2002; 227(1-2):145-51. View