Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 119 | 2024
Research Articles
HIV-1 controllers exhibit an enhanced antiretroviral innate state characterised by overexpression of p21 and MCPIP1 and silencing of ERVK-6 RNA expression
1Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de AIDS & Imunologia Molecular, Rio de Janeiro, RJ, Brasil
2Fundação Oswaldo Cruz-Fiocruz, Instituto Nacional de Infectologia Evandro Chagas, Laboratório de Pesquisa Clínica em DST/AIDS, Rio de Janeiro, RJ, Brasil
3Universidade Federal do Espírito Santo, Centro de Ciências da Saúde, Departamento de Patologia, Laboratório de Genômica e Ecologia Viral, Vitória, ES, Brasil
4Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Imunofarmacologia, Rio de Janeiro, RJ, Brasil
5Fundação Oswaldo Cruz-Fiocruz, Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas, Rio de Janeiro, RJ, Brasil
6Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Arbovírus e Vírus Hemorrágicos, Rio de Janeiro, RJ, Brasil
DOI: 10.1590/0074-02760240071
625 views
951 downloads
ABSTRACT
BACKGROUND Human immunodeficiency virus (HIV)-1 infection can activate the expression of human endogenous retroviruses (HERVs), particularly HERV-K (HML-2). HIV controllers (HICs) are rare people living with HIV (PLWHs) who naturally control HIV-1 replication and overexpress some cellular restriction factors that negatively regulate the LTR-driven transcription of HIV-1 proviruses.
OBJECTIVES To understand the ability of HICs to control the expression of endogenous retroviruses.
METHODS We measured endogenous retrovirus type K6 (ERVK-6) RNA expression in peripheral blood mononuclear cells (PBMCs) of HICs (n = 23), antiretroviral (ART)-suppressed subjects (n = 8), and HIV-1-negative (NEG) individuals (n = 10) and correlated the transcript expression of ERVK-6 with multiple HIV-1 cellular restriction factors.
FINDINGS Our study revealed that ERVK-6 RNA expression in PBMCs from HICs was significantly downregulated compared with that in both the ART and NEG control groups. Moreover, we detected that ERVK-6 RNA levels in PBMCs across all groups were negatively correlated with the expression levels of p21 and MCPIP1, two cellular restriction factors that limit the activation of macrophages and T cells by downregulating the activity of NF-kB.
MAIN CONCLUSIONS These findings support the hypothesis that HICs activate innate antiviral mechanisms that may simultaneously downregulate the transcription of both exogenous (HIV-1) and endogenous (ERVK-6) retroviruses. Future studies with larger cohorts should be performed to confirm this hypothesis and to explore the role of p21 and MCPIP1 in regulating HERV-K expression in physiological and pathological conditions.
REFERENCES
01. Jern P, Coffin JM. Effects of retroviruses on host genome function. Annu Rev Genet. 2008; 42(1): 709-32.
02. Agoni L, Guha C, Lenz J. Detection of human endogenous retrovirus K (HERV-K) transcripts in human prostate cancer cell lines. Front Oncol. 2013; 3: 180.
03. Cegolon L, Salata C, Weiderpass E, Vineis P, Palù G, Mastrangelo G. Human endogenous retroviruses and cancer prevention: evidence and prospects. BMC Cancer. 2013; 13(1): 4.
04. Bhardwaj N, Maldarelli F, Mellors J, Coffin JM. HIV-1 Infection leads to increased transcription of human endogenous retrovirus HERV-K (HML-2) proviruses in vivo but not to increased virion production. J Virol. 2014; 88(19): 11108-20.
05. Argaw-Denboba A, Balestrieri E, Serafino A, Cipriani C, Bucci I, Sorrentino R, et al. HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features. J Exp Clin Cancer Res. 2017; 36(1): 20.
06. Douville R, Liu J, Rothstein J, Nath A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol. 2011; 69(1): 141-51.
07. Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015; 7(307): 307ra153.
08. Balada E, Vilardell-Tarrés M, Ordi-Ros J. Implication of human endogenous retroviruses in the development of autoimmune diseases. Int Rev Immunol. 2010; 29(4): 351-70.
09. Temerozo JR, Fintelman-Rodrigues N, Dos Santos MC, Hottz ED, Sacramento CQ, Da Silva APD, et al. Human endogenous retrovirus K in the respiratory tract is associated with COVID-19 physiopathology. Microbiome. 2022; 10(1): 65.
10. Costas J. Evolutionary dynamics of the human endogenous retrovirus family HERV-K inferred from full-length proviral genomes. J Mol Evol. 2001; 53(3): 237-43.
11. Subramanian RP, Wildschutte JH, Russo C, Coffin JM. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology. 2011; 8(1): 90.
12. Young GR, Terry SN, Manganaro L, Cuesta-Dominguez A, Deikus G, Bernal-Rubio D, et al. HIV-1 infection of primary CD4 + T cells regulates the expression of specific human endogenous retrovirus HERV-K (HML-2) elements. J Virol. 2018; 92(1): e01507-17.
13. Contreras-Galindo R, López P, Vélez R, Yamamura Y. HIV-1 infection increases the expression of human endogenous retroviruses type K (HERV-K) in vitro. AIDS Res Human Retroviruses. 2007; 23(1): 116-22.
14. Vincendeau M, Göttesdorfer I, Schreml JMH, Wetie AGN, Mayer J, Greenwood AD, et al. Modulation of human endogenous retrovirus (HERV) transcription during persistent and de novo HIV-1 infection. Retrovirology. 2015; 12(1): 27.
15. Jones RB, Garrison KE, Mujib S, Mihajlovic V, Aidarus N, Hunter DV, et al. HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. J Clin Invest. 2012; 122(12): 4473-89.
16. Ormsby CE, SenGupta D, Tandon R, Deeks SG, Martin JN, Jones RB, et al. Human endogenous retrovirus expression is inversely associated with chronic immune activation in HIV-1 infection. PLoS One. 2012; 7(8): e41021.
17. Contreras-Galindo R, Kaplan MH, Markovitz DM, Lorenzo E, Yamamura Y. Detection of HERV-K(HML-2) viral RNA in plasma of HIV type 1-infected individuals. AIDS Res Hum Retroviruses. 2006; 22(10): 979-84.
18. Contreras-Galindo R, Almodóvar-Camacho S, González-Ramírez S, Lorenzo E, Yamamura Y. Comparative longitudinal studies of HERV-K and HIV-1 RNA titers in HIV-1-infected patients receiving successful versus unsuccessful highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2007; 23(9): 1083-6.
19. Garrison KE, Jones RB, Meiklejohn DA, Anwar N, Ndhlovu LC, Chapman JM, et al. T cell responses to human endogenous retroviruses in HIV-1 infection. PLoS Pathog. 2007; 3(11): e165.
20. Gonzalez-Hernández MJ, Swanson MD, Contreras-Galindo R, Cookinham S, King SR, Noel RJ, et al. Expression of human endogenous retrovirus type K (HML-2) is activated by the tat protein of HIV-1. J Virol. 2012; 86(15): 7790-805.
21. Russ E, Mikhalkevich N, Iordanskiy S. Expression of human endogenous retrovirus group K (HERV-K) HML-2 correlates with immune activation of macrophages and type I interferon response. Microbiol Spectr. 2023; 11(2): e04438-22.
22. Hurst T, Magiorkinis G. Epigenetic control of human endogenous retrovirus expression: focus on regulation of long-terminal repeats (LTRs). Viruses. 2017; 9(6): 130.
23. De Azevedo SSD, Ribeiro-Alves M, Côrtes FH, Delatorre E, Spangenberg L, Naya H, et al. Increased expression of CDKN1A/ p21 in HIV-1 controllers is correlated with upregulation of ZC3H12A/MCPIP1. Retrovirology. 2020; 17(1): 18.
24. Fu M, Blackshear PJ. RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. Nat Rev Immunol. 2017;17(2):130–43.
25. Sun X, Feng W, Guo Y, Wang Q, Dong C, Zhang M, et al. MCPIP1 attenuates the innate immune response to influenza A virus by suppressing RIG‐I expression in lung epithelial cells. J Med Virol. 2018; 90(2): 204-11.
26. Chen X, Zhao Q, Xie Q, Xing Y, Chen Z. MCPIP1 negatively regulate cellular antiviral innate immune responses through DUB and disruption of TRAF3-TBK1-IKKε complex. Biochem Biophy Res Commun. 2018; 503(2): 830-6.
27. Lloberas J, Celada A. p21waf1/CIP1, a CDK inhibitor and a negative feedback system that controls macrophage activation. Eur J Immunol. 2009; 39(3): 691-4.
28. Scatizzi JC, Mavers M, Hutcheson J, Young B, Shi B, Pope RM, et al. The CDK domain of p21 is a suppressor of IL-1β-mediated inflammation in activated macrophages. Eur J Immunol. 2009; 39(3): 820-5.
29. Trakala M, Arias CF, García MI, Moreno-Ortiz MC, Tsilingiri K, Fernández PJ, et al. Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1). Eur J Immunol. 2009; 39(3): 810-9.
30. De Azevedo SSD, Caetano DG, Côrtes FH, Teixeira SLM, Dos Santos Silva K, Hoagland B, et al. Highly divergent patterns of genetic diversity and evolution in proviral quasispecies from HIV controllers. Retrovirology. 2017; 14(1): 29.
31. Côrtes FH, De Paula HHS, Bello G, Ribeiro-Alves M, De Azevedo SSD, Caetano DG, et al. Plasmatic levels of IL-18, IP-10, and activated CD8+ T cells are potential biomarkers to identify HIV-1 elite controllers with a true functional cure profile. Front Immunol. 2018; 9: 1576.
32. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7): research0034.1.
33. Solari A, Salmaso L, Pesarin F, Basso D, editors. Permutation tests for stochastic ordering and ANOVA. Theory and applications with R. Lecture Notes in Statistics. Vol. 194. London, New York: Springer; 2009. 217pp.
34. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. Available from: https://www.R-project.org/.
35. Lê S, Josse J, Husson F. FactoMineR : an R package for multivariate analysis. J Stat Soft. 2008; 25(1): 1-18.
36. Kassambara A, Mundt F. factoextra: extract and visualize the results of multivariate data analyses. 2016 [cited 2024]. Available from: https://CRAN.R-project.org/package=factoextra.
37. Mantovani F, Kitsou K, Paraskevis D, Lagiou P, Magiorkinis G. The interaction of human immunodeficiency virus-1 and human endogenous retroviruses in patients (primary cell cultures) and cell line models. Microbiol Spectr. 2023; 11(6): e01379-23.
38. Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, Hunt PW, et al. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol. 2009; 83(1): 329-35.
39. Landay A, Golub ET, Desai S, Zhang J, Winkelman V, Anastos K, et al. HIV RNA levels in plasma and cervical-vaginal lavage fluid in elite controllers and HAART recipients. AIDS. 2014; 28(5): 739-43.
40. Bergamaschi A, David A, Le Rouzic E, Nisole S, Barré-Sinoussi F, Pancino G. The CDK Inhibitor p21Cip1/WAF1 is induced by FcγR activation and restricts the replication of human immunodeficiency virus type 1 and related primate lentiviruses in human macrophages. J Virol. 2009; 83(23): 12253-65.
41. Valle-Casuso JC, Allouch A, David A, Lenzi GM, Studdard L, Barré-Sinoussi F, et al. p21 restricts HIV-1 in monocyte-derived dendritic cells through the reduction of deoxynucleoside triphosphate biosynthesis and regulation of SAMHD1 antiviral activity. J Virol. 2017; 91(23): e01324-17.
42. Liu S, Qiu C, Miao R, Zhou J, Lee A, Liu B, et al. MCPIP1 restricts HIV infection and is rapidly degraded in activated CD4+ T cells. Proc Natl Acad Sci USA. 2013; 110(47): 19083-8.
43. Allouch A, David A, Amie SM, Lahouassa H, Chartier L, Margottin- Goguet F, et al. p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway. Proc Natl Acad Sci USA. 2013; 110(42): E3997-4006.
44. Lin RJ, Chien HL, Lin SY, Chang BL, Yu HP, Tang WC, et al. MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation. Nucleic Acids Res. 2013; 41(5): 3314-26.
45. Jura J, Skalniak L, Koj A. Monocyte chemotactic protein-1-induced protein-1 (MCPIP1) is a novel multifunctional modulator of inflammatory reactions. Biochim Biophys Acta. 2012; 1823(10): 1905-13.
46. Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez- Cuellar E, Kuniyoshi K, et al. Malt1-induced cleavage of regnase- 1 in CD4+ helper T cells regulates immune activation. Cell. 2013; 153(5): 1036-49.
47. Chan JK, Greene WC. Dynamic roles for NF‐κB in HTLV‐I and HIV‐1 retroviral pathogenesis. Immunol Rev. 2012; 246(1): 286-310.
48. Manghera M, Douville RN. Endogenous retrovirus-K promoter: a landing strip for inflammatory transcription factors? Retrovirology. 2013; 10(1): 16.
49. Rosa A, Chande A, Ziglio S, De Sanctis V, Bertorelli R, Goh SL, et al. HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature. 2015; 526(7572): 212-7.
50. Usami Y, Wu Y, Göttlinger HG. SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature. 2015; 526(7572): 218-23.
51. Zeng C, Waheed AA, Li T, Yu J, Zheng YM, Yount JS, et al. SERINC proteins potentiate antiviral type I IFN production and proinflammatory signaling pathways. Sci Signal. 2021; 14(700): eabc7611.
52. Di Giorgio E, Xodo LE. Endogenous retroviruses (ERVs): Does RLR (RIG-I-like receptors)-MAVS pathway directly control senescence and aging as a consequence of ERV de-repression? Front Immunol. 2022; 13: 917998.
53. Min X, Zheng M, Yu Y, Wu J, Kuang Q, Hu Z, et al. Ultraviolet light induces HERV expression to activate RIG-I signalling pathway in keratinocytes. Exp Dermatol. 2022; 31(8): 1165-1176.
54. Mikhalkevich N, O’Carroll IP, Tkavc R, Lund K, Sukumar G, Dalgard CL, et al. Response of human macrophages to gamma radiation is mediated via expression of endogenous retroviruses. Johnson WE, editor. PLoS Pathog. 2021; 17(2): e1009305.
55. Liu X, Liu Z, Wu Z, Ren J, Fan Y, Sun L, et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell. 2023; 186(2): 287-304.e26.
56. Li M, Kao E, Gao X, Sandig H, Limmer K, Pavon-Eternod M, et al. Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature. 2012; 491(7422): 125-8.
57. Yang S, Zhan Y, Zhou Y, Jiang Y, Zheng X, Yu L, et al. Interferon regulatory factor 3 is a key regulation factor for inducing the expression of SAMHD1 in antiviral innate immunity. Sci Rep. 2016; 6(1): 29665.
58. Pauli EK, Schmolke M, Hofmann H, Ehrhardt C, Flory E, Münk C, et al. High level expression of the anti-retroviral protein APOBEC3G is induced by influenza A virus but does not confer antiviral activity. Retrovirology. 2009; 6(1): 38.
59. De Mulder M, SenGupta D, Deeks SG, Martin JN, Pilcher CD, Hecht FM, et al. Anti-HERV-K (HML-2) capsid antibody responses in HIV elite controllers. Retrovirology. 2017; 14(1): 41.
60. SenGupta D, Tandon R, Vieira RGS, Ndhlovu LC, Lown-Hecht R, Ormsby CE, et al. Strong human endogenous retrovirus-specific T cell responses are associated with control of HIV-1 in chronic infection. J Virol. 2011; 85(14): 6977-85.
61. Bailey JR, Williams TM, Siliciano RF, Blankson JN. Maintenance of viral suppression in HIV-1–infected HLA-B*57+ elite suppressors despite CTL escape mutations. J Exp Med. 2006; 203(5): 1357-69.
62. Mens H, Kearney M, Wiegand A, Shao W, Schønning K, Gerstoft J, et al. HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J Virol. 2010; 84(24): 12971-81.
63. Salgado M, Brennan TP, O’Connell KA, Bailey JR, Ray SC, Siliciano RF, et al. Evolution of the HIV-1 nefgene in HLA-B*57 positive elite suppressors. Retrovirology. 2010; 7(1): 94.
64. O’Connell KA, Brennan TP, Bailey JR, Ray SC, Siliciano RF, Blankson JN. Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. J Virol. 2010; 84(14): 7018-28.
65. Pernas M, Tarancón-Diez L, Rodríguez-Gallego E, Gómez J, Prado JG, Casado C, et al. Factors leading to the loss of natural elite control of HIV-1 infection. J Virol. 2018; 92(5): e01805-17.
66. Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, et al. Multiple origins of virus persistence during natural control of HIV infection. Cell. 2016; 166(4): 1004-15.
67. Utay NS, Douek DC. Interferons and HIV infection: the good, the bad, and the ugly. Pathog Immun. 2016; 1(1): 107-16.
68. Doyle T, Goujon C, Malim MH. HIV-1 and interferons: who’s interfering with whom? Nat Rev Microbiol. 2015; 13(7): 403-13.
69. Russ E, Iordanskiy S. Endogenous retroviruses as modulators of innate immunity. Pathogens. 2023; 12(2): 162.
70. Côrtes FH, Passaes CPB, Bello G, Teixeira SLM, Vorsatz C, Babic D, et al. HIV Controllers with different viral load cutoff levels have distinct virologic and immunologic profiles. J Acquir Immune Defic Syndr. 2015; 68(4): 377-85.
71. Caetano DG, Ribeiro-Alves M, Hottz ED, Vilela LM, Cardoso SW, Hoagland B, et al. Increased biomarkers of cardiovascular risk in HIV-1 viremic controllers and low persistent inflammation in elite controllers and art-suppressed individuals. Sci Rep. 2022 ;12(1): 6569.
72. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page- Shafer K, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008; 197(1): 126-33.
73. Krishnan S, Wilson EMP, Sheikh V, Rupert A, Mendoza D, Yang J, et al. Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis. 2014; 209(6): 931-9.
74. Pereyra F, Lo J, Triant VA, Wei J, Buzon MJ, Fitch KV, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS. 2012; 26(18): 2409-12.
75. Noel N, Boufassa F, Lécuroux C, Saez-Cirion A, Bourgeois C, Dunyach-Remy C, et al. Elevated IP10 levels are associated with immune activation and low CD4+ T-cell counts in HIV controller patients. AIDS. 2014; 28(4): 467-76.
76. Platten M, Jung N, Trapp S, Flossdorf P, Meyer-Olson D, Zur Wiesch JS, et al. Cytokine and chemokine signature in elite versus viremic controllers infected with HIV. AIDS Res Human Retroviruses. 2016; 32(6): 579-87.
77. Neuhaus J, Jacobs Jr DR, Baker JV, Calmy A, Duprez D, La Rosa A, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010; 201(12): 1788-95.
78. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011; 62(1): 141-55.
79. Hocini H, Bonnabau H, Lacabaratz C, Lefebvre C, Tisserand P, Foucat E, et al. HIV controllers have low inflammation associated with a strong HIV-specific immune response in blood. J Virol. 2019; 93(10): e01690-18.
80. Singh M, Leddy SM, Iñiguez LP, Bendall ML, Nixon DF, Feschotte C. Transposable elements may enhance antiviral resistance in HIV-1 elite controllers. bioRxiv [Preprint]. 2023. Available from: http://biorxiv.org/lookup/doi/10.1101/2023.12.11.571123.
81. Grandi N, Pisano MP, Scognamiglio S, Pessiu E, Tramontano E. Comprehensive analysis of HERV transcriptome in HIV+ cells: absence of HML2 activation and general downregulation of individual HERV loci. Viruses. 2020; 12(4): 481.
82. Gonzalez-Hernandez MJ, Cavalcoli JD, Sartor MA, Contreras- Galindo R, Meng F, Dai M, et al. Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 tat protein. J Virol. 2014; 88(16): 8924-35.
Financial support: FAPERJ (Grant no. E-26/110.123/2014), CNPq (Grant no. 401220/2016-8).
SSDA is financed by a postdoctoral fellowship from the “Pós-Doutorado Nota 10 (PDR 10)” by FAPERJ (Grant no. E-26/202.335/2019); GB is funded by CNPq (Grant no. 304883/2020-4) and FAPERJ (Grant no. E-26/202.896/2018).
+ Corresponding author: suwellendias@gmail.com 
https://orcid.org/0000-0001-6681-0987
Received 01 April 2024
Accepted 12 July 2024
HOW TO CITE
de Azevedo SSD, Ribeiro-Alves M, Côrtes FH, Delatorre E, Hoagland B, Villela LM, et al. HIV-1 controllers exhibit an enhanced antiretroviral innate state characterised by overexpression of p21 and MCPIP1 and silencing of ERVK-6 RNA expression. Mem Inst Oswaldo Cruz. 2024; 119: e240071.
