Project B3: Thomas Harrer & Christiane Krystelle Nganou-Makamdop

Virology

Head of Institute:
Prof. Dr. med. Klaus Überla

Induction of Nef-resistant HIV-1-specific CTL responses as a new strategy for the development of HIV-1-specific therapeutic vaccines

As cure of HIV-1 infection requires the eradication of viral reservoirs (Estes et al., 2017; Rothenberger MK, 2015), cure strategies should include boosting of cytotoxic T lymphocytes (CTL) to eliminate infected cells. HIV-1 can evade CTL recognition by Nef-mediated down-regulation of HLA-A/B-expression and Vpu-mediated downregulation of HLA-C. This could explain the failure of T cell-based vaccines to prevent HIV‑1 infection and to improve control of viremia (Harrer E et al., 2005; Dinges et al., 2016; Harrer et al., 2018). The negative effect of Nef on CTL epitope presentation varies between the various CTL epitopes as Nef-mediated down-regulation of HLA-A/B is not complete. Own experiments demonstrated that some viral peptides are “resistant” to the negative effects of Nef, as they are still presented to CTL despite low HLA-I expression presumably due to highly efficient processing of the peptides from viral proteins and high binding affinity to the HLA molecules.

In our research project, we are investigating the induction of HIV-1-specific CTL targeting Nef/Vpu-“resistant” CTL epitopes which are still presented to CTL despite the negative effects of Nef and Vpu. For this purpose, we have developed techniques allowing the efficient mapping of Nef/Vpu-“resistant” epitopes. Furthermore, we will analyze whether the recognition of such epitopes correlates to a better suppression of HIV-1 replication and to a better course of HIV-1-infection. The results of this project shall contribute to the development of more efficient HIV-1 vaccines and immunotherapies.

References

  • Dinges W, Girard PM, Podzamczer D, Brockmeyer NH, García F, Harrer T, Lelievre JD, Frank I, Colin De Verdière N, Yeni GP, Ortega Gonzalez E, Rubio R, Clotet Sala B, DeJesus E, Pérez-Elias MJ, Launay O, Pialoux G, Slim J, Weiss L, Bouchaud O, Felizarta F, Meurer A, Raffi F, Esser S, Katlama C, Koletar SL, Mounzer K, Swindells S, Baxter JD, Schneider S, Chas J, Molina JM, Koutsoukos M, Collard A, Bourguignon P, Roman F (2016). The F4/AS01B HIV-1 vaccine candidate is safe and immunogenic, but does not show viral efficacy in antiretroviral therapy-naive, HIV-1-infected adults: a randomized controlled trial. Medicine 95: e2673.
  • Estes J, Kityo C, Ssali F, Swainson L, Nganou-Makamdop K, Del Prete G, Deeks S, Luciw P, Chipman J, Beilman B, Hoskuldsson T, Khoruts A, Anderson J, Deleage C, Jasurda J, Schmidt T, Hafertepe M, Callisto S, Pearson H, Reimann T, Schuster J, Schoephoerster J, Southern P, Perkey K, Shang L, Wietgrefe S, Fletcher C, Lifson J, Douek D, McCune J, Haase A, Schacker T (2017). Defining total-body AIDS-virus Burden with implications for curative strategies. Nat Med 23: 1271-1276
  • Etschel JK, Hückelhoven AG, Hofmann C, Zitzelsberger K, Maurer K, Bergmann S, Mueller-Schmucker SM, Wittmann J, Spriewald BM, Dörrie J, Schaft N, Harrer T (2012). HIV-1 mRNA electroporation of PBMC: A simple and efficient method to monitor T-cell responses against autologous HIV-1 in HIV-1-infected patients. J Immunol Methods 380: 40-55.
  • Harrer E, Bauerle M, Ferstl B, Chaplin P, Petzold B, Mateo L, Handley A, Tzatzaris M, Vollmar J, Bergmann S, Rittmaier M; Eismann K; Müller S, Kalden JR, Spriewald B, Willbold D, Harrer T (2005). Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 10, 285-300.
  • Harrer T, Dinges W, Roman F; TH-HIV-011 study group (2018). Long-term follow-up of HIV-1-infected adults who received the F4/AS01B HIV-1 vaccine candidate in two randomised controlled trials. Vaccine 36: 2683-2686.
  • Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ, Chipman JG, Khoruts A, Estes JD, Anderson J, Callisto SP, Schmidt TE, Thorkelson A, Reilly C, Perkey K, Reimann TG, Utay NS, Nganou Makamdop K, Stevenson M, Douek DC, Haase AT, Schacker TW (2015). Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci USA 112: E1126-1134.
 
Contact
Prof. Dr. med. Thomas Harrer
phone: +49 9131 85-34742
e-mail: thomas.harrer@uk-erlangen.de
business card
Dr. Christiane Krystelle Nganou-Makamdop
phone: +49 9131 85-22678
e-mail: krystelle.nganou@uk-erlangen.de
business card