HIV-1C and HIV-1B Tat protein polymorphism in Southern Brazil

Abstract

The transactivator of transcription (Tat) is a key HIV regulatory protein. We aimed to identify the frequency of key polymorphisms in HIV-1C compared with HIV-1B Tat protein, chiefly in the cysteine-, arginine-, and glutamine-rich domains and identify novel point mutations in HIV-1B and C sequences from Southern Brazil. This study was the first to investigate the genetic diversity and point mutations within HIV-1 Tat C in a Brazilian cohort. This was an observational, cross-sectional study, which included sequences of HIV-1B (n = 20) and HIV-1C (n = 21) from Southern Brazil. Additionally, 344 HIV-1C sequences were obtained from the Los Alamos database: 29 from Brazil and 315 from Africa, Asia, and Europe. The frequency of C31S substitution on HIV-1 Tat C in Brazil was 82% vs. 10% in the HIV-1B group (p < 0.0001). The frequency of the R57S substitution among the HIV-1C sequences from Brazil was 74% vs. 20% in HIV-1B (p = 0.004), and that of substitution Q63E in HIV-1C was 80% and 20% in HIV-1B (p < 0.0001). The mutation P60Q was more frequent in HIV-1B than in HIV-1C (55% and 6.12%, respectively, p < 0.0001)). Novel point mutations in the HIV-1C and B Tat functional domains were described. The frequency of C31S and other key point mutations in HIV-1 Tat C in Brazil were similar to those described in Africa, although lower than those in India. The Tat-B and C sequences found in Southern Brazil are consistent with biological differences and have potential implications for HIV-1 subtype pathogenesis.

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References

  1. Albini A, Benelli R, Giunciuglio D, Cai T, Mariani G, Ferrini S, Noonan DM (1998) Identification of a novel domain of HIV tat involved in monocyte chemotaxis. J Biol Chem 273:15895–15900

    CAS  PubMed  Article  Google Scholar 

  2. Beall CJ, Mahajan S, Kuhn DE, Kolattukudy PE (1996) Site-directed mutagenesis of monocyte chemoattractant protein-1 identifies two regions of the polypeptide essential for biological activity. Biochem J 313:633–640

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Bello G, Passaes CP, Guimarães ML, Lorete RS, Matos Almeida SE, Medeiros RM, Alencastro PR, Morgado MG (2008) Origin and evolutionary history of HIV-1 subtype C in Brazil. AIDS 22:1993–2000

    PubMed  Article  Google Scholar 

  4. Brasil, Ministério da Saúde (2018) Programa Nacional de DST/AIDS.http://www.aids.gov.br/assistencia/manualdst/item12.html

  5. Canducci F, Marinozzi MC, Sampaolo M, Berrè S, Bagnarelli P, Degano M, Gallotta G, Mazzi B, Lemey P, Burioni R, Clementi M (2009) Dynamic features of the selective pressure on the human immunodeficiency virus type 1 (HIV-1) gp120 CD4-binding site in a group of long term non progressor (LTNP) subjects. Retrovirology 6:4. https://doi.org/10.1186/1742-4690-6-4

  6. Carroll R, Martarano L, Derse D (1991) Identification of lentivirus Tat functional domains through generation of equine infectious anemia virus/human immunodeficiency virus type 1 tat gene chimera. J Virol 65:3460–3467

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Chang YN, Jeang KT (1992) The basic RNA-binding domain of HIV-2 Tat contributes to preferential trans-activation of a TAR2-containing LTR. Nucleic Acids Res 20:5465–5472

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121

    CAS  PubMed  Article  Google Scholar 

  9. Dampier W, Nonnemacher MR, Mell J, Earl J, Ehrlich GD, Pirrone V, Aiamkitsumrit B, Zhong W, Kercher K, Passic S, Williams JW, Jacobson JM, Wigdahl B (2016) HIV-1 genetic variation resulting in the development of new quasispecies continues to be encountered in the peripheral blood of well-suppressed patients. PLoS One 11:e0155382. https://doi.org/10.1371/journal.pone.01553-82

  10. Darbinian N, Darbinyan A, Czernik M, Peruzzi F, Khalili K, Reiss K, Gordon J, Amini S (2008) HIV-1 Tat inhibits NGF-induced Egr-1 transcriptional activity and consequent p35 expression in neural cells. J Cell Physiol 216:128–134

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. de Almeida SM, Ribeiro CE, de Pereira AP, Badiee J, Cherner M, Smith D, Maich I, Raboni SM, Rotta I, Barbosa FJ, Heaton RK, Umlauf A, Ellis RJ (2013) Neurocognitive impairment in HIV-1 subtype C versus B-infected individuals in Southern Brazil. J Neurovirol 19:550–556

    PubMed  PubMed Central  Article  Google Scholar 

  12. de Almeida SM, Rotta I, Ribeiro CE, Oliveira MF, Chaillon A, de Pereira AP, Cunha AP, Zonta M, Bents JF, Raboni SM, Smith D, Letendre S, Ellis RJ (2017) Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization: case study. J Neurovirol 23:460–473

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. de Almeida SM, Oliveira MF, Chaillon A, Rotta I, Ribeiro CE, de Pereira AP, Smith D, Letendre S, Ellis RJ (2018) Transient and asymptomatic meningitis in human immunodeficiency virus-1 subtype C: a case study of genetic compartmentalization and biomarker dynamics. J Neurovirol 24:786–796

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. de Almeida SM, Rotta I, Ribeiro CE, Smith D, Wang R, Judicello J, Potter M, Vaida F, Letendre S, Ellis RJ (2016) Blood-CSF barrier and compartmentalization of CNS cellular immune response in HIV infection. J Neuroimmunol 301:41–48

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. de Almeida SM, Rotta I, Jiang Y, Li X, Raboni SM, Ribeiro CE, Smith D, Potter M, Vaida F, Letendre S, Ellis RJ (2016) Biomarkers of chemotaxis and inflammation in cerebrospinal fluid and serum in individuals with HIV-1 subtype C versus B. J Neurovirol 22:715–724

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. de Almeida SM, Rotta I, de Pereira AP, Tang B, Umlauf A, Ribeiro CEL, Letendre S, Ellis RJ (2020) Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape. J Neurovirol 26:241–251

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  17. Derse D, Carvalho M, Carroll R, Peterlin BM (1991) A minimal lentivirus tat. J Virol 65:7012–7015

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Dingwall C, Ernberg I, Gait MJ, Green SM, Heaphy S, Karn J, Lowe AD, Singh M, Skinner MA, Valerio R (1989) Human immunodeficiency virus 1 tat protein binds trans-activation responsive region (TAR) RNA in vitro. Proc Natl Acad Sci USA 86:6925–6929

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P (1993) Gallo RC (1993) Release, uptake and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Guimarães ML, Marques BCL, Bertoni N, Teixeira SLM, Morgado MG (2015) Assessing the HIV-1 epidemic in Brazilian drug users: a molecular epidemiology approach. PLoS ONE 10:e0141372

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. Gurwitz KT, Burman RJ, Murugan BD, Garnett S, Ganief T, Soares NC, Raimondo JV, Blackburn JM (2017) Time-dependent, HIV-Tat-induced perturbation of human neurons in vitro: towards a model for the molecular pathology of HIV-associated neurocognitive disorders. Front Mol Neurosci 10:163

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Hauber J, Malim MH, Cullen BR (1989) Mutational analysis of the conserved basic domain of human immunodeficiency virus tat protein. J Virol 63:1181–1187

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Koken SE, Greijer AE, Verhoef K, van Wamel J, Bukrinskaya AG, Berkhout B (1994) Intracellular analysis of in vitro modified HIV tat protein. J Biol Chem 269:8366–8375

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. Konings FA, Burda ST, Urbanski MM, Zhong P, Nadas A, Nyambi PN (2006) Human immunodeficiency virus type 1 (HIV-1) circulating recombinant form 02_AG (CRF02_AG) has a higher in vitro replicative capacity than its parental subtypes A and G. J Med Virol 78:523–534

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. Kurosu T, Mukai T, Komoto S, Ibrahim MS, Li YG, Kobayashi T, Tsuji S, Ikuta K (2002) Human immunodeficiency virus type 1 subtype C exhibits higher transactivation activity of tat than subtypes B and E. Microbiol Immunol 46:787–799

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. Letendre SL, FitzSimons C, Ellis RJ, Clifford D, Collier AC, Gelman B, Marra C, McArthur J, McCutchan JA, Morgello S, Simpson D, Vaida F, Heaton R, Grant I (2010) Correlates of CSF Viral Loads in 1,221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections

  27. Li W, Huang Y, Reid R, Steiner J, Malpica-Llanos T, Darden TA, Shankar SK, Mahadevan A, Satishchandra P, Nath A (2008) NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci 28:12190–12198

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Li GH, Li W, Mumper RJ, Nath A (2012) Molecular mechanisms in the dramatic enhancement of HIV-1 Tat transduction by cationic liposomes. FASEB J 26:2824–2834

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Magnuson DSK, Knudsen BE, Geiger JD, Brownstone RM, Nath A (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37:373–380

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186:S193–S198

    CAS  PubMed  Article  Google Scholar 

  31. Neogi U, Bontell I, Shet A, De Costa A, Gupta S, Diwan V, Laishram RS, Wanchu A, Ranga U, Banerjea AC, Sönnerborg A (2012) Molecular epidemiology of HIV-1 subtypes in India: origin and evolutionary history of the predominant subtype C. PLoS ONE 7:e39819

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Ortega M, Heaps JM, Joska J, Vaida F, Seedat S, Stein DJ, Paul R, Ances BM (2013) HIV clades B and C are associated with reduced brain volumetrics. J Neurovirol 19:479–487

    PubMed  Article  PubMed Central  Google Scholar 

  33. Park IW, Wang JF, Groopman JE (2001) HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes. Blood 97:352–358

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. Paul RH, Joska JA, Woods C, Seedat S, Engelbrecht S, Hoare J, Heaps J, Valcour V, Ances B, Baker LM, Salminen LE, Stein DJ (2014) Impact of the HIV Tat C30C31S dicysteine substitution on neuropsychological function in patients with clade C disease. J Neurovirol 20:627–635

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Paul RH, Phillips S, Hoare J, Laidlaw DH, Cabeen R, Olbricht GR, Su Y, Stein DJ, Engelbrecht S, Seedat S, Salminen LE (2017) Neuroimaging abnormalities in clade C HIV are independent of Tat genetic diversity. J Neurovirol 23:319–328

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Prabhakar B, Banu A, Pavithra HB, Chandrashekhara P, Sasthri S (2011) Immunological failure despite virological suppression in HIV seropositive individuals on antiretroviral therapy. Indian J Sex Transm Dis AIDS 32:94–98

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Raboni SM, Almeida SM, Rotta I, Ribeiro CEL, Rosario D, Vidal LR, Nogueira MB, Riedel M, Winhescki MG, Ferreira KA, Ellis R (2010) Molecular epidemiology of HIV-1 clades in Southern Brazil. Mem Inst Oswaldo Cruz 105:1044–1049

    PubMed  PubMed Central  Article  Google Scholar 

  38. Ranga U, Shankarappa R, Siddappa NB, Ramakrishna L, Nagendran R, Mahalingam M, Mahadevan A, Jayasuryan N, Satishchandra P, Shankar SK, Prasad VR (2004) Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokine. J Virol 78:2586–2590

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Rao VR, Neogi U, Talboom JS, Padilla L, Rahman M, Fritz-French C, Gonzalez-Ramirez S, Verma A, Wood C, Ruprecht RM, Ranga U, Azim T, Joska J, Eugenin E, Shet A, Bimonte-Nelson H, Tyor WR, Prasad VR (2013) Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence. Retrovirology 10:61. https://doi.org/10.1186/1742-4690-10-61

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Rappaport J, Lee SJ, Khalili K, Wong-Staal F (1989) The acidic amino-terminal region of HIV-1 tat protein constitutes an essential activating domain. New Biologist 1:101–110

    CAS  Google Scholar 

  41. Rayne F, Debaisieux S, Yezid H, Lin YL, Mettling C, Konate K, Chazal N, Arold ST, Pugnière M, Sanchez F, Bonhoure A, Briant L, Loret E, Roy C, Beaumelle B (2010) Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J 29:1348–1362

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Rhee SY, Fessel WJ, Zolopa AR, Hurley L, Liu T, Taylor J, Nguyen DP, Slome S, Klein D, Horberg M, Flamm J, Follansbee S, Schapiro JM, Shafer RW (2005) HIV-1 Protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug resistance surveillance. J Infect Dis 192:456–465

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Ronsard L, Lata S, Singh J, Ramachandran VG, Das S, Banerjea AC (2014) Molecular and genetic characterization of natural HIV-1 Tat exon-1 variants from North India and their functional implications. PLoS ONE 9:e85452

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Roy CN, Khandaker I, Oshitani H (2015) Intersubtype genetic variation of HIV-1 Tat exon 1. AIDS Res Hum Retroviruses 31:641–648

    CAS  PubMed  Article  Google Scholar 

  45. Roy CN, Khandaker I, Oshitani H (2015b) Evolutionary dynamics of Tat in HIV-1 subtypes B and C. PLoS One 10:e0129896. https://doi.org/10.1371/journal.pone.01298-96

  46. Ruben S, Perkins A, Purcell R, Joung K, Sia R, Burghoff R, Haseltine WA, Rosen CA (1989) Structural and functional characterization of human immunodeficiency virus tat protein. J Virol 63:1–8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Ruiz AP, Ajasin DO, Ramasamy S, DesMarais V, Eugenin EA, Prasad VR (2019) A naturally occurring polymorphism in the HIV-1 tat basic domain inhibits uptake by bystander cells and leads to reduced neuroinflammation. Sci Rep 9:3308

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. Satishchandra P, Nalini A, Gourie-Devi M, Khanna N, Santosh V, Ravi V, Desai A, Chandramuki A, Jayakumar PN, Shankar SK (2000) Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India (1989–96). Indian J Med Res 111:14–23

    CAS  PubMed  Google Scholar 

  49. Shankarappa R, Chatterjee R, Learn GH, Neogi D, Ding M, Roy P, Ghosh A, Kingsley L, Harrison L, Mullins JI, Gupta P (2001) Human immunodeficiency virus type 1 env sequences from Calcutta in eastern India: identification of features that distinguish subtype C sequences in India from other subtype C sequences. J Virol 75:10479–10487

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Siddappa NB, Venkatramanan M, Venkatesh P, Janki MV, Jayasuryan N, Desai A, Ravi V, Ranga U (2006) Transactivation and signaling functions of Tat are not correlated: biological and immunological characterization of HIV-1 subtype-C Tat protein. Retrovirology 3:53. https://doi.org/10.1186/1742-4690-3-53

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Spector C, Mele AR, Wigdahl B, Nonnemacher MR (2019) Genetic variation and function of the HIV-1 Tat protein. Med Microbiol Immunol 208:131–169

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. Weeks KM, Crothers DM (1991) RNA recognition by Tat-derived peptides: interaction in the major groove? Cell 66:577–588

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. Weiss JM, Nath A, Major EO, Berman JW (1999) HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol 163:2953–2959

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Williams ME, Zulu SS, Stein DJ, Joska JA, Naudé PJW (2020) Signatures of HIV-1 subtype B and C Tat proteins and their effects in the neuropathogenesis of HIV-associated neurocognitive impairments. Neurobiology of Disease 136:104701

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. Witten JA, Thomas KG, Westgarth-Taylor J, Joska JA (2015) Executive dyscontrol of learning and memory: findings from a Clade C HIV-positive South African sample. The Clinical Neuropsychologist 29:956–984

    PubMed  Article  PubMed Central  Google Scholar 

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Funding

CFAR (International Pilot Grant P30 AI036214 and CFAR Visiting Researcher Grant PTHMON7) and NIMH (R21 MH076651-01).

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Sérgio Monteiro de Almeida—concept, data collection and analysis, manuscript organization and writing; Indianara Rotta—concept, data collection and analysis, sequencing and phylogenetic analysis; Luine Rosele Renaud Vidal—concept and sequencing; Jucelia Stadinicki dos Santos—sequencing and phylogenetic analysis; Avindra Nath—manuscript review; Kory Johnson—phylogenetic analysis; Scott Letendre—manuscript review; Ronald J. Ellis—concept, manuscript review.

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de Almeida, S.M., Rotta, I., Vidal, L.R.R. et al. HIV-1C and HIV-1B Tat protein polymorphism in Southern Brazil. J. Neurovirol. (2021). https://doi.org/10.1007/s13365-020-00935-z

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Keywords

  • Subtype C
  • HIV-1
  • Tat
  • Dicysteine
  • Neuropathogenesis
  • Polymorphism