HIV-1 Accessory Proteins: Which one is Potentially Effective in Diagnosis and Vaccine Development?

Author(s): Alireza Milani, Kazem Baesi, Elnaz Agi, Ghazal Marouf, Maryam Ahmadi, Azam Bolhassani*

Journal Name: Protein & Peptide Letters

Volume 28 , Issue 6 , 2021


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Abstract:

Background: The combination antiretroviral therapy (cART) could increase the number of circulating naive CD4 T lymphocytes, but was not able to eradicate human immunodeficiency virus-1 (HIV-1) infection.

Objective: Thus, induction of strong immune responses is important for control of HIV-1 infection. Furthermore, a simple and perfect serological method is required to detect virus in untreated-, treated- and drug resistant- HIV-1 infected individuals.

Methods: This study was conducted to assess and compare immunogenic properties of Nef, Vif, Vpr and Vpu accessory proteins as an antigen candidate in mice and their diagnostic importance in human as a biomarker.

Results: Our data showed that in mice, all heterologous prime/ boost regimens were more potent than homologous prime/ boost regimens in eliciting Th1 response and Granzyme B secretion as CTL activity. Moreover, the Nef, Vpu and Vif proteins could significantly increase Th1 immune response. In contrast, the Vpr protein could considerably induce Th2 immune response. On the other hand, among four accessory proteins, HIV-1 Vpu could significantly detect treated group from untreated group as a possible biomarker in human.

Conclusion: Generally, among accessory proteins, Nef, Vpu and Vif antigens were potentially more suitable vaccine antigen candidates than Vpr antigen. Human antibodies against all these proteins were higher in HIV-1 different groups than healthy group. Among them, Vpu was known as a potent antigen in diagnosis of treated from untreated individuals. The potency of accessory proteins as an antigen candidate in an animal model and a human cohort study are underway.

Keywords: HIV-1, accessory protein, diagnosis, therapeutic vaccine, delivery system, cell penetrating peptide.

[1]
Arya, S.; Lal, P.; Singh, P.; Kumar, A. Recent advances in diagnosis of HIV and future prospects. Indian J. Biotechnol., 2015, 14, 9-18.
[2]
de Goede, A.L.; Vulto, A.G.; Osterhaus, A.D.; Gruters, R.A. Understanding HIV infection for the design of a therapeutic vaccine. Part I: epidemiology and pathogenesis of HIV infection. Ann. Pharm. Fr., 2015, 73(2), 87-99.
[http://dx.doi.org/10.1016/j.pharma.2014.11.002] [PMID: 25496723]
[3]
Lehmann, M.H.; Lehmann, J.M.; Erfle, V. Nef-induced CCL2 expression contributes to HIV/SIV brain invasion and neuronal dysfunction. Front. Immunol., 2019, 10, 2447.
[http://dx.doi.org/10.3389/fimmu.2019.02447] [PMID: 31681324]
[4]
Goncalves, J.; Silva, F.; Freitas-Vieira, A.; Santa-Marta, M.; Malhó, R.; Yang, X.; Gabuzda, D.; Barbas, C., III Functional neutralization of HIV-1 Vif protein by intracellular immunization inhibits reverse transcription and viral replication. J. Biol. Chem., 2002, 277(35), 32036-32045.
[http://dx.doi.org/10.1074/jbc.M201906200] [PMID: 12039955]
[5]
Quaranta, M.G.; Mattioli, B.; Giordani, L.; Viora, M. Immunoregulatory effects of HIV-1 Nef protein. Biofactors, 2009, 35(2), 169-174.
[http://dx.doi.org/10.1002/biof.28] [PMID: 19449444]
[6]
Kikuchi, T.; Iwabu, Y.; Tada, T.; Kawana-Tachikawa, A.; Koga, M.; Hosoya, N.; Nomura, S.; Brumme, Z.L.; Jessen, H.; Pereyra, F.; Trocha, A.; Walker, B.D.; Iwamoto, A.; Tokunaga, K.; Miura, T. Anti-APOBEC3G activity of HIV-1 Vif protein is attenuated in elite controllers. J. Virol., 2015, 89(9), 4992-5001.
[http://dx.doi.org/10.1128/JVI.03464-14] [PMID: 25717111]
[7]
Bahraoui, E.; Benjouad, A.; Sabatier, J.M.; Allain, J.P.; Laurian, Y.; Montagnier, L.; Gluckman, J.C. Relevance of anti-nef antibody detection as an early serologic marker of human immunodeficiency virus infection. Blood, 1990, 76(1), 257-264.
[http://dx.doi.org/10.1182/blood.V76.1.257.257] [PMID: 1694699]
[8]
García, F.; León, A.; Gatell, J.M.; Plana, M.; Gallart, T. Therapeutic vaccines against HIV infection. Hum. Vaccin. Immunother., 2012, 8(5), 569-581.
[http://dx.doi.org/10.4161/hv.19555] [PMID: 22634436]
[9]
DeVico, A.L.; Gallo, R.C. Control of HIV-1 infection by soluble factors of the immune response. Nat. Rev. Microbiol., 2004, 2(5), 401-413.
[http://dx.doi.org/10.1038/nrmicro878] [PMID: 15100693]
[10]
Ranasinghe, S.; Soghoian, D.Z.; Lindqvist, M.; Ghebremichael, M.; Donaghey, F.; Carrington, M.; Seaman, M.S.; Kaufmann, D.E.; Walker, B.D.; Porichis, F. HIV-1 antibody neutralization breadth is associated with enhanced HIV-specific CD4+ T cell responses. J. Virol., 2015, 90(5), 2208-2220.
[http://dx.doi.org/10.1128/JVI.02278-15] [PMID: 26656715]
[11]
Rosa, D.S.; Ribeiro, S.P.; Almeida, R.R.; Mairena, E.C.; Postól, E.; Kalil, J.; Cunha-Neto, E. A DNA vaccine encoding multiple HIV CD4 epitopes elicits vigorous polyfunctional, long-lived CD4+ and CD8+ T cell responses. PLoS One, 2011, 6(2), e16921.
[http://dx.doi.org/10.1371/journal.pone.0016921] [PMID: 21347287]
[12]
Virgin, H.W.; Walker, B.D. Immunology and the elusive AIDS vaccine. Nature, 2010, 464(7286), 224-231.
[http://dx.doi.org/10.1038/nature08898] [PMID: 20220841]
[13]
Bolhassani, A. Potential efficacy of cell-penetrating peptides for nucleic acid and drug delivery in cancer. Biochim. Biophys. Acta, 2011, 1816(2), 232-246.
[PMID: 21840374]
[14]
Lee, S.; Nguyen, M.T. Recent advances of vaccine adjuvants for infectious diseases. Immune Netw., 2015, 15(2), 51-57.
[http://dx.doi.org/10.4110/in.2015.15.2.51] [PMID: 25922593]
[15]
Rosa, D.S.; Apostolico, J.; Boscardin, S.B. DNA vaccines: how much have we accomplished in the last 25 years. J. Vaccines Vaccin., 2015, 6, 3.
[16]
Wedrychowicz, H. Antiparasitic DNA vaccines in 21st century. Acta Parasitol., 2015, 60(2), 179-189.
[http://dx.doi.org/10.1515/ap-2015-0026] [PMID: 26203983]
[17]
Kardani, K.; Milani, A.; H Shabani, S.; Bolhassani, A. Cell penetrating peptides: the potent multi-cargo intracellular carriers. Expert Opin. Drug Deliv., 2019, 16(11), 1227-1258.
[http://dx.doi.org/10.1080/17425247.2019.1676720] [PMID: 31583914]
[18]
Rostami, B.; Irani, S.; Bolhassani, A.; Cohan, R.A. Gene and protein delivery using four cell penetrating peptides for HIV-1 vaccine development. IUBMB Life, 2019, 71(10), 1619-1633.
[http://dx.doi.org/10.1002/iub.2107] [PMID: 31220406]
[19]
Ponnappan, N.; Budagavi, D.P.; Chugh, A. CyLoP-1: membrane-active peptide with cell-penetrating and antimicrobial properties. Biochim. Biophys. Acta Biomembr., 2017, 1859(2), 167-176.
[http://dx.doi.org/10.1016/j.bbamem.2016.11.002] [PMID: 27836642]
[20]
Ponnappan, N.; Chugh, A. Cell-penetrating and cargo-delivery ability of a spider toxin-derived peptide in mammalian cells. Eur. J. Pharm. Biopharm., 2017, 114, 145-153.
[http://dx.doi.org/10.1016/j.ejpb.2017.01.012] [PMID: 28159722]
[21]
Kardani, K.; Bolhassani, A.; Shahbazi, S. Prime-boost vaccine strategy against viral infections: mechanisms and benefits. Vaccine, 2016, 34(4), 413-423.
[http://dx.doi.org/10.1016/j.vaccine.2015.11.062] [PMID: 26691569]
[22]
Baesi, K.; Moallemi, S.; Ravanshad, M. Phylogenetic analysis of HIV-1 pol gene: first subgenomic evidence of CRf29-BF among Iranian HIV-1 patients. Asian Pac. J. Trop. Dis., 2014, 4, S617-S620.
[http://dx.doi.org/10.1016/S2222-1808(14)60690-3]
[23]
Baesi, K.; Ravanshad, M.; Ghanbarisafari, M.; Saberfar, E.; Seyedalinaghi, S.; Volk, J.E. Antiretroviral drug resistance among antiretroviral-naïve and treatment experienced patients infected with HIV in Iran. J. Med. Virol., 2014, 86(7), 1093-1098.
[http://dx.doi.org/10.1002/jmv.23898] [PMID: 24740443]
[24]
Davoodi, S.; Bolhassani, A.; Sadat, S.M.; Irani, S. Enhancing HIV-1 Nef penetration into mammalian cells as an antigen candidate. JOMMID, 2019, 7, 37-43.
[http://dx.doi.org/10.29252/JoMMID.7.1.2.37]
[25]
Ramezani, A.; Aghakhani, A.; Soleymani, S.; Bavand, A.; Bolhassani, A. Significance of serum antibodies against HPV E7, Hsp27, Hsp20 and Hp91 in Iranian HPV-exposed women. BMC Infect. Dis., 2019, 19(1), 142.
[http://dx.doi.org/10.1186/s12879-019-3780-2] [PMID: 30755156]
[26]
Namazi, F.; Bolhassani, A.; Sadat, S.M.; Irani, S. Histidine-rich nona-arginine and Latarcin 1 peptide successfully deliver HIV-1 Nef antigen in vitro. JOMMID, 2019, 7, 107-115.
[http://dx.doi.org/10.29252/JoMMID.7.4.107]
[27]
Bolhassani, A.; Zahedifard, F.; Taghikhani, M.; Rafati, S. Enhanced immunogenicity of HPV16E7 accompanied by Gp96 as an adjuvant in two vaccination strategies. Vaccine, 2008, 26(26), 3362-3370.
[http://dx.doi.org/10.1016/j.vaccine.2008.03.082] [PMID: 18471945]
[28]
Kardani, K.; Hashemi, A.; Bolhassani, A. Comparative analysis of two HIV-1 multiepitope polypeptides for stimulation of immune responses in BALB/c mice. Mol. Immunol., 2020, 119, 106-122.
[http://dx.doi.org/10.1016/j.molimm.2020.01.013] [PMID: 32007753]
[29]
Kardani, K.; Hashemi, A.; Bolhassani, A. Comparison of HIV-1 Vif and Vpu accessory proteins for delivery of polyepitope constructs harboring Nef, Gp160 and P24 using various cell penetrating peptides. PLoS One, 2019, 14(10), e0223844.
[http://dx.doi.org/10.1371/journal.pone.0223844] [PMID: 31671105]
[30]
Abdollahi, A.; Saffar, H. The diagnosis of HIV infection in infants and children. Iran. J. Pathol., 2016, 11(2), 89-96.
[PMID: 27499768]
[31]
Ferdin, J.; Goričar, K.; Dolžan, V.; Plemenitaš, A.; Martin, J.N.; Peterlin, B.M.; Deeks, S.G.; Lenassi, M. Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA. PLoS One, 2018, 13(1), e0191613.
[http://dx.doi.org/10.1371/journal.pone.0191613] [PMID: 29364927]
[32]
Lee, J.H.; Schierer, S.; Blume, K.; Dindorf, J.; Wittki, S.; Xiang, W.; Ostalecki, C.; Koliha, N.; Wild, S.; Schuler, G.; Fackler, O.T.; Saksela, K.; Harrer, T.; Baur, A.S. HIV-Nef and ADAM17-containing plasma extracellular vesicles induce and correlate with immune pathogenesis in chronic HIV infection. EBioMedicine, 2016, 6, 103-113.
[http://dx.doi.org/10.1016/j.ebiom.2016.03.004] [PMID: 27211553]
[33]
Raymond, A.D.; Campbell-Sims, T.C.; Khan, M.; Lang, M.; Huang, M.B.; Bond, V.C.; Powell, M.D. HIV Type 1 Nef is released from infected cells in CD45(+) microvesicles and is present in the plasma of HIV-infected individuals. AIDS Res. Hum. Retroviruses, 2011, 27(2), 167-178.
[http://dx.doi.org/10.1089/aid.2009.0170] [PMID: 20964480]
[34]
Greenway, A.L.; Mills, J.; Rhodes, D.; Deacon, N.J.; McPhee, D.A. Serological detection of attenuated HIV-1 variants with nef gene deletions. AIDS, 1998, 12(6), 555-561.
[http://dx.doi.org/10.1097/00002030-199806000-00003] [PMID: 9583594]
[35]
Wieland, U.; Kühn, J.E.; Jassoy, C.; Rübsamen-Waigmann, H.; Wolber, V.; Braun, R.W. Antibodies to recombinant HIV-1 vif, tat, and nef proteins in human sera. Med. Microbiol. Immunol. (Berl.), 1990, 179(1), 1-11.
[http://dx.doi.org/10.1007/BF00190145] [PMID: 2184337]
[36]
Reiss, P.; de Ronde, A.; Lange, J.M.; de Wolf, F.; Dekker, J.; Debouck, C.; Goudsmit, J. Antibody response to the viral negative factor (nef) in HIV-1 infection: a correlate of levels of HIV-1 expression. AIDS, 1989, 3(4), 227-233.
[http://dx.doi.org/10.1097/00002030-198904000-00006] [PMID: 2500956]
[37]
Madhavi, V.; Wines, B.D.; Amin, J.; Emery, S.; Lopez, E.; Kelleher, A.; Center, R.J.; Hogarth, P.M.; Chung, A.W.; Kent, S.J.; Stratov, I. ENCORE1 Study Group; Sydney LTNP Study Group. HIV-1 Env- and Vpu-specific antibody-dependent cellular cytotoxicity responses associated with elite control of HIV. J. Virol., 2017, 91(18), e00700-e00717.
[http://dx.doi.org/10.1128/JVI.00700-17] [PMID: 28701393]
[38]
Hoshino, S.; Sun, B.; Konishi, M.; Shimura, M.; Segawa, T.; Hagiwara, Y.; Koyanagi, Y.; Iwamoto, A.; Mimaya, J.; Terunuma, H.; Kano, S.; Ishizaka, Y. Vpr in plasma of HIV type 1-positive patients is correlated with the HIV type 1 RNA titers. AIDS Res. Hum. Retroviruses, 2007, 23(3), 391-397.
[http://dx.doi.org/10.1089/aid.2006.0124] [PMID: 17411372]
[39]
Reiss, P.; Lange, J.M.; de Ronde, A.; de Wolf, F.; Dekker, J.; Danner, S.A.; Debouck, C.; Goudsmit, J. Antibody response to viral proteins U (vpu) and R (vpr) in HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. (1988), 1990, 3(2), 115-122.
[PMID: 2136912]
[40]
Ayyavoo, V.; Muthumani, K.; Kudchodkar, S.; Zhang, D.; Ramanathan, P.; Dayes, N.S.; Kim, J.J.; Sin, J.I.; Montaner, L.J.; Weiner, D.B. HIV-1 viral protein R compromises cellular immune function in vivo. Int. Immunol., 2002, 14(1), 13-22.
[http://dx.doi.org/10.1093/intimm/14.1.13] [PMID: 11751747]
[41]
Tähtinen, M.; Strengell, M.; Collings, A.; Pitkänen, J.; Kjerrström, A.; Hakkarainen, K.; Peterson, P.; Kohleisen, B.; Wahren, B.; Ranki, A.; Ustav, M.; Krohn, K. DNA vaccination in mice using HIV-1 nef, rev and tat genes in self-replicating pBN-vector. Vaccine, 2001, 19(15-16), 2039-2047.
[http://dx.doi.org/10.1016/S0264-410X(00)00420-5] [PMID: 11228375]
[42]
Du, J.; Wu, X.; Long, F.; Wen, J.; Hao, W.; Chen, R.; Kong, X.; Qian, M.; Jiang, W. Improvement in efficacy of DNA vaccine encoding HIV-1 Vif by LIGHT gene adjuvant. Viral Immunol., 2013, 26(1), 68-74.
[http://dx.doi.org/10.1089/vim.2012.0073] [PMID: 23330678]
[43]
Pujals, S.; Sabidó, E.; Tarragó, T.; Giralt, E. all-D proline-rich cell-penetrating peptides: a preliminary in vivo internalization study. Biochem. Soc. Trans., 2007, 35(Pt 4), 794-796.
[http://dx.doi.org/10.1042/BST0350794] [PMID: 17635150]
[44]
Saleh, T.; Bolhassani, A.; Shojaosadati, S.A.; Aghasadeghi, M.R. MPG-based nanoparticle: an efficient delivery system for enhancing the potency of DNA vaccine expressing HPV16E7. Vaccine, 2015, 33(28), 3164-3170.
[http://dx.doi.org/10.1016/j.vaccine.2015.05.015] [PMID: 26001433]
[45]
Karpenko, L.I.; Nekrasova, N.A.; Ilyichev, A.A.; Lebedev, L.R.; Ignatyev, G.M.; Agafonov, A.P.; Zaitsev, B.N.; Belavin, P.A.; Seregin, S.V.; Danilyuk, N.K.; Babkina, I.N.; Bazhan, S.I. Comparative analysis using a mouse model of the immunogenicity of artificial VLP and attenuated Salmonella strain carrying a DNA-vaccine encoding HIV-1 polyepitope CTL-immunogen. Vaccine, 2004, 22(13-14), 1692-1699.
[http://dx.doi.org/10.1016/j.vaccine.2003.09.050] [PMID: 15068852]
[46]
Yoo, J.W.; Doshi, N.; Mitragotri, S. Adaptive micro and nanoparticles: temporal control over carrier properties to facilitate drug delivery. Adv. Drug Deliv. Rev., 2011, 63(14-15), 1247-1256.
[http://dx.doi.org/10.1016/j.addr.2011.05.004] [PMID: 21605607]
[47]
Lembo, D.; Cavalli, R. Nanoparticulate delivery systems for antiviral drugs. Antivir. Chem. Chemother., 2010, 21(2), 53-70.
[http://dx.doi.org/10.3851/IMP1684] [PMID: 21107015]
[48]
Rodríguez, A.M.; Pascutti, M.F.; Maeto, C.; Falivene, J.; Holgado, M.P.; Turk, G.; Gherardi, M.M. IL-12 and GM-CSF in DNA/MVA immunizations against HIV-1 CRf12_BF Nef induced T-cell responses with an enhanced magnitude, breadth and quality. PLoS One, 2012, 7(5), e37801.
[http://dx.doi.org/10.1371/journal.pone.0037801] [PMID: 22655069]
[49]
Casella, C.R.; Rapaport, E.L.; Finkel, T.H. Vpu increases susceptibility of human immunodeficiency virus type 1-infected cells to fas killing. J. Virol., 1999, 73(1), 92-100.
[http://dx.doi.org/10.1128/JVI.73.1.92-100.1999] [PMID: 9847311]
[50]
Asbach, B.; Kibler, K.V.; Köstler, J.; Perdiguero, B.; Yates, N.L.; Stanfield-Oakley, S.; Tomaras, G.D.; Kao, S.F.; Foulds, K.E.; Roederer, M.; Seaman, M.S.; Montefiori, D.C.; Parks, R.; Ferrari, G.; Forthal, D.N.; Phogat, S.; Tartaglia, J.; Barnett, S.W.; Self, S.G.; Gottardo, R.; Cristillo, A.D.; Weiss, D.E.; Galmin, L.; Ding, S.; Heeney, J.L.; Esteban, M.; Jacobs, B.L.; Pantaleo, G.; Wagner, R. Priming with a potent HIV-1 DNA vaccine frames the quality of immune responses prior to a poxvirus and protein boost. J. Virol., 2019, 93(3), e01529-e18.
[PMID: 30429343]
[51]
Asakura, Y.; Hamajima, K.; Fukushima, J.; Mohri, H.; Okubo, T.; Okuda, K. Induction of HIV-1 Nef-specific cytotoxic T lymphocytes by Nef-expressing DNA vaccine. Am. J. Hematol., 1996, 53(2), 116-117.
[http://dx.doi.org/10.1002/(SICI)1096-8652(199610)53:2<116::AID-AJH9>3.0.CO;2-2] [PMID: 8892736]


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VOLUME: 28
ISSUE: 6
Year: 2021
Published on: 24 June, 2021
Page: [687 - 698]
Pages: 12
DOI: 10.2174/0929866528999201231213610
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