The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Individuals
2.2. Study Samples
2.3. MDDC’s Generation
2.4. Flow Cytometry
2.5. Transfection: Electroporation of MDDCs with Unmodified/Modified mRNA TMEP-B
2.6. Detection of Unmodified/Modified TMEP-B mRNA Expression by Flow Cytometry
2.7. Blocking PD1 Expression on T-Cells
2.8. Co-Cultures: Electroporated DCs with Autologous Lymphocytes
2.9. Cytokine Secretion Analysis
2.10. Statistical Analysis
3. Results
3.1. TMEP-B Affected DCs Maturation
3.2. Flag Expression on DCs Transfected with TMEP-B and TMEP-Bmod
3.3. CCR7 Expression on iDCs and mDCs after mRNA Transfection
3.4. T-Cells Proliferation Induced by mRNA Electroporation
3.5. Cytokine and Chemokine Secretion Induced by mRNA
3.6. Combining TMEP-B with Nivolumab and Vesatolimod Improved HIV-Specific T-Cells Proliferation
3.7. Cytokines and Chemokines That Promote Viral Control Increase after TMEP-B or TMEP-Bmod Are Combined with Nivolumab or Vesatolimod
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Palella, F.J., Jr.; Delaney, K.M.; Moorman, A.C.; Loveless, M.O.; Fuhrer, J.; Satten, G.A.; Aschman, D.J.; Holmberg, S.D. Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. N. Engl. J. Med. 1998, 338, 853–860. [Google Scholar] [CrossRef] [PubMed]
- Board, N.L.; Moskovljevic, M.; Wu, F.; Siliciano, R.F.; Siliciano, J.D. Engaging innate immunity in HIV-1 cure strategies. Nat. Rev. Immunol. 2022, 22, 499–512. [Google Scholar] [CrossRef] [PubMed]
- Ward, A.R.; Mota, T.M.; Jones, R.B. Immunological approaches to HIV cure. Semin. Immunol. 2021, 51, 101412. [Google Scholar] [CrossRef] [PubMed]
- Bailon, L.; Mothe, B.; Berman, L.; Brander, C. Novel Approaches Towards a Functional Cure of HIV/AIDS. Drugs 2020, 80, 859–868. [Google Scholar] [CrossRef] [PubMed]
- Davenport, M.P.; Khoury, D.S.; Cromer, D.; Lewin, S.R.; Kelleher, A.D.; Kent, S.J. Functional cure of HIV: The scale of the challenge. Nat. Rev. Immunol. 2019, 19, 45–54. [Google Scholar] [CrossRef] [PubMed]
- Perdiguero, B.; Raman, S.C.; Sánchez-Corzo, C.S.; Sorzano, C.O.; Valverde, J.R.; Esteban, M.; Gómez, C.E. Potent HIV-1-specific CD8 T cell responses induced in mice after priming with a multiepitopic DNA-TMEP and boosting with the HIV vaccine MVA-B. Viruses 2018, 10, 424. [Google Scholar] [CrossRef] [Green Version]
- Perdiguero, B.; Sánchez-Corzo, C.S.; Sorzano, C.O.; Mediavilla, P.; Saiz, L.; Esteban, M.; Gómez, C.E. Induction of broad and polyfunctional HIV-1-specific T cell responses by the multiepitopic protein TMEP-B vectored by MVA virus. Vaccines 2019, 7, 57. [Google Scholar] [CrossRef] [Green Version]
- Mothe, B.; Manzardo, C.; Sanchez-Bernabeu, A.; Coll, P.; Morón-López, S.; Puertas, M.C.; Hanke, T. Corrigendum to ‘Therapeutic vaccination refocuses T-cell responses towards conserved regions of HIV-1 in early treated individuals (BCN 01 study)’ EClinicalMedicine 11 (2019) 65–80. EClinicalMedicine 2020, 18, 100250. [Google Scholar] [CrossRef] [PubMed]
- Mothe, B.; Rosás-Umbert, M.; Coll, P.; Manzardo, C.; Puertas, M.C.; Morón-López, S. HIVconsv vaccines and romidepsin in early-treated HIV-1-infected individuals: Safety, immunogenicity and effect on the viral reservoir (Study BCN02). Front. Immunol. 2020, 11, 823. [Google Scholar] [CrossRef]
- Pardi, N.; Hogan, M.J.; Porter, F.W.; Weissman, D. mRNA vaccines–a new era in vaccinology. Nat. Rev. Drug Discov. 2018, 17, 261–279. [Google Scholar] [CrossRef] [PubMed]
- Esteban, I.; Pastor-Quiñones, C.; Usero, L.; Plana, M.; García, F.; Leal, L. In the era of mRNA vaccines, is there any hope for hiv functional cure? Viruses 2021, 13, 501. [Google Scholar] [CrossRef]
- Karikó, K.; Buckstein, M.; Ni, H.; Weissman, D. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005, 23, 165–175. [Google Scholar] [CrossRef] [Green Version]
- Karikó, K.; Muramatsu, H.; Welsh, F.A.; Ludwig, J.; Kato, H.; Akira, S.; Weissman, D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 2008, 16, 1833–1840. [Google Scholar] [CrossRef]
- Karikó, K.; Muramatsu, H.; Ludwig, J.; Weissman, D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 2011, 39, e142. [Google Scholar] [CrossRef] [Green Version]
- Hou, X.; Zaks, T.; Langer, R.; Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 2021, 6, 1078–1094. [Google Scholar] [CrossRef]
- Liu, T.; Liang, Y.; Huang, L. Development and Delivery Systems of mRNA Vaccines. Front. Bioeng. Biotechnol. 2021, 9, 718753. [Google Scholar] [CrossRef]
- Ramachandran, S.; Satapathy, S.R.; Dutta, T. Delivery Strategies for mRNA Vaccines. Pharm. Med. 2022, 36, 11–20. [Google Scholar] [CrossRef]
- Chaudhary, N.; Weissman, D.; Whitehead, K.A. mRNA vaccines for infectious diseases: Principles, delivery and clinical translation. Nat. Rev. Drug Discov. 2021, 20, 817–838. [Google Scholar] [CrossRef]
- Seddiki, N.; Lévy, Y. Therapeutic HIV-1 vaccine: Time for immunomodulation and combinatorial strategies. Curr. Opin. HIV AIDS 2018, 13, 119–127. [Google Scholar] [CrossRef] [PubMed]
- Borducchi, E.N.; Cabral, C.; Stephenson, K.E.; Liu, J.; Abbink, P.; Ng’ang’a, D.; Barouch, D.H. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 2016, 540, 284–287. [Google Scholar] [CrossRef]
- Tsai, A.; Irrinki, A.; Kaur, J.; Cihlar, T.; Kukolj, G.; Sloan, D.D.; Murry, J.P. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy. J. Virol. 2017, 91, e02166-e16. [Google Scholar] [CrossRef] [Green Version]
- Meijerink, H.; Indrati, A.R.; Soedarmo, S.; Utami, F.; de Jong, C.A.; Alisjahbana, B.; Van der Ven, A.J. Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency. AIDS 2018, 32, 1491–1497. [Google Scholar] [CrossRef]
- Pen, J.J.; Keersmaecker, B.D.; Heirman, C.; Corthals, J.; Liechtenstein, T.; Escors, D.; Breckpot, K. Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther. 2014, 21, 262–271. [Google Scholar] [CrossRef]
- Fromentin, R.; Bakeman, W.; Lawani, M.B.; Khoury, G.; Hartogensis, W.; DaFonseca, S.; Chomont, N. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART. PLoS Pathog. 2016, 12, e1005761. [Google Scholar] [CrossRef] [Green Version]
- Fromentin, R.; DaFonseca, S.; Costiniuk, C.T.; El-Far, M.; Procopio, F.A.; Hecht, F.M.; Chomont, N. PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals. Nat. Commun. 2019, 10, 814. [Google Scholar] [CrossRef] [Green Version]
- Gómez, C.E.; Perdiguero, B.; Usero, L.; Marcos-Villar, L.; Miralles, L.; Leal, L.; Esteban, M. Enhancement of the HIV-1-Specific Immune Response Induced by an mRNA Vaccine through Boosting with a Poxvirus MVA Vector Expressing the Same Antigen. Vaccines 2021, 9, 959. [Google Scholar] [CrossRef]
- Osa, A.; Uenami, T.; Koyama, S.; Fujimoto, K.; Okuzak, D. Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. JCI Insight 2018, 3, e59125. [Google Scholar] [CrossRef]
- Cocchi, F.; DeVico, A.L.; Garzino-Demo, A.; Arya, S.K.; Gallo, R.C.; Lusso, P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995, 270, 1811–1815. [Google Scholar] [CrossRef] [Green Version]
- Gebre, M.S.; Rauch, S.; Roth, N.; Yu, J.; Chandrashekar, A.; Mercado, N.B.; Barouch, D.H. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine. Nature 2022, 601, 410–414. [Google Scholar] [CrossRef]
- Liang, Q.; Wang, Y.; Zhang, S.; Sun, J.; Sun, W.; Li, J.; Zhang, L. RBD trimer mRNA vaccine elicits broad and protective immune responses against SARS-CoV-2 variants. iScience 2022, 25, 104043. [Google Scholar] [CrossRef]
- Lim, S.Y.; Osuna, C.E.; Hraber, P.T.; Hesselgesser, J.; Gerold, J.M.; Barnes, T.L.; Whitney, J.B. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci. Transl. Med. 2018, 10, eaao4521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Riddler, S.A.; Para, M.; Benson, C.A.; Mills, A.; Ramgopal, M.; DeJesus, E.; SenGupta, D. Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living with Human Immunodeficiency Virus-1. Clin. Infect. Dis. 2021, 72, e815–e824. [Google Scholar] [CrossRef] [PubMed]
- SenGupta, D.; Brinson, C.; DeJesus, E.; Mills, A.; Shalit, P.; Guo, S.; Deeks, S.G. The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy. Sci. Transl. Med. 2021, 13, eabg3071. [Google Scholar] [CrossRef]
- Day, C.L.; Kaufmann, D.E.; Kiepiela, P.; Brown, J.A.; Moodley, E.S. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006, 443, 350–354. [Google Scholar] [CrossRef]
- Banga, R.; Procopio, F.A.; Noto, A.; Pollakis, G.; Cavassini, M.; Ohmiti, K. PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 2016, 22, 754–761. [Google Scholar] [CrossRef] [PubMed]
- Velu, V.; Titanji, K.; Zhu, B.; Husain, S.; Pladevega, A.; Lai, L.; Amara, R.R. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2009, 458, 206–210. [Google Scholar] [CrossRef] [Green Version]
- Mylvaganam, G.H.; Chea, L.S.; Tharp, G.K.; Hicks, S.; Velu, V.; Iyer, S.S.; Amara, R.R. Combination anti-PD-1 and antiretroviral therapy provides therapeutic benefit against SIV. JCI Insight 2018, 3, e122940. [Google Scholar] [CrossRef] [PubMed]
- Pan, E.; Feng, F.; Li, P.; Yang, Q.; Ma, X.; Wu, C.; Sun, C. Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys. Front. Immunol. 2018, 9, 2415. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Usero, L.; Leal, L.; Gómez, C.E.; Miralles, L.; Aurrecoechea, E.; Esteban, I.; Torres, B.; Inciarte, A.; Perdiguero, B.; Esteban, M.; et al. The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. Vaccines 2023, 11, 286. https://doi.org/10.3390/vaccines11020286
Usero L, Leal L, Gómez CE, Miralles L, Aurrecoechea E, Esteban I, Torres B, Inciarte A, Perdiguero B, Esteban M, et al. The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. Vaccines. 2023; 11(2):286. https://doi.org/10.3390/vaccines11020286
Chicago/Turabian StyleUsero, Lorena, Lorna Leal, Carmen Elena Gómez, Laia Miralles, Elena Aurrecoechea, Ignasi Esteban, Berta Torres, Alexy Inciarte, Beatriz Perdiguero, Mariano Esteban, and et al. 2023. "The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses" Vaccines 11, no. 2: 286. https://doi.org/10.3390/vaccines11020286
APA StyleUsero, L., Leal, L., Gómez, C. E., Miralles, L., Aurrecoechea, E., Esteban, I., Torres, B., Inciarte, A., Perdiguero, B., Esteban, M., García, F., & Plana, M. (2023). The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. Vaccines, 11(2), 286. https://doi.org/10.3390/vaccines11020286