Advancing HIV-1 cure strategies by integrating cell-intrinsic innate immunity during latency reversal

Abstract

While combinatory antiretroviral therapy (cART) has dramatically improved the life expectancy and quality of people living with HIV-1 (PLHIV), neither a protective vaccine exists nor can HIV-1 infection be cured. Cessation of cART leads to rebound of viremia within a few weeks. HIV-1 persists in reservoirs even in the presence of cART, predominantly in latently infected, long-lived resting CD4+ memory Tcells. HIV-1 infection involves integration of viral DNA in the genome of infected cells with limited, if at all, expression of viral RNA and proteins. Latently infected cells may thus be immunologically indistinguishable from uninfected cells and not susceptible to cytolytic killing. Many cure efforts have focused on the “shock-and-kill” approach aiming at purging the virus reservoir. Specifically, a “shock” event is supposed to reactivate HIV-1 transcription and protein production to make cells immunologically visible and therefore susceptible for the “kill” event. The aim of the project is to improve our understanding of HIV-1 latency establishment, maintenance and reversal. Using cell models of HIV-1 latency and primary CD4+ T-cells from PLHIV, we will characterize the role of cell-intrinsic innate immunity in the context of HIV-1 latency and how treatment with individual latency-reverting agents modulate the cellular milieu, with either beneficial or unfavourable implications for the “shock-and-kill” approach.

Where does the project lie on the Translational Pathway?

T1 – Basic Research

T2 Human / Clinical Research

Expected Outputs

Training Opportunities

Hands-on training in all above mentioned methods by experienced members of the group. Furthermore, the student will be encouraged to learn additional methods beneficial to the project in the context of collaborations, and will have full access to soft skills trainings (self-organization, communication, presentation etc.)

Skills Required

Background in virology and/or immunology. Interest in conducting basic research in order to contribute to close a clinical knowledge gap (HIV-1 cure)

Key Publications associated with this project

Single Cell RNA-Sequencing-based Analysis of CD4+ T-Cell Subset-Specific Susceptibility to Transcriptional Modulation by HIV-1 Latency-Reversing Agents, Kazmierski, J., Postmus, D., Wyler, E., Fischer, C., Jansen, J., Meixenberger, K., Vitcetz, S.N., Sohn, M., Sauer, S., Bannert, N., Landthaler, M., Goffinet, C.*, bioRxiv, posted 5 June 2023, doi: https://www.biorxiv.org/content/10.1101/2020.05.04.075119v2.full 2. A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913, Kazmierski, J., Elsner, C., Doehner, K., Xu, S., Ducroux, A., Pott, F., Jansen, J., Thorball, C.W., Zeymer, O., Zhou, X., Fedorov, R., Fellay, J., Loeffler, M.W., Weber, A.N.R., Sodeik, B., Goffinet, C., Journal of Immunology, ji2100685 (2022) 3. Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells, Elsner, C.# , Ponnurangam, A.# , Kazmierski, J., Zillinger, T., Jansen, J., Todt, D., Döhner, K., Xu, S., Ducroux, A., Kriedemann, N., Malassa, A., Larsen, P.K., Hartmann, G., Barchet, W., Steinmann, E., Kalinke, U., Sodeik, B., Goffinet, C., Proceedings of the National Academy of Sciences, 117(32):19475 (2020) 4. cGAS-mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites, Xu, S.# , Ducroux, A.# , Ponnurangam, A., Franz, S., Vieyres, G., Müsken, M., Zillinger, T., Malassa, A., Ewald, E., Hornung, V., Barchet, W., Häussler, S., Pietschmann, T., Goffinet, C., Cell Host & Microbe, 20(4):443 (2016)

A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913, Kazmierski, J., Elsner, C., Doehner, K., Xu, S., Ducroux, A., Pott, F., Jansen, J., Thorball, C.W., Zeymer, O., Zhou, X., Fedorov, R., Fellay, J., Loeffler, M.W., Weber, A.N.R., Sodeik, B., Goffinet, C., Journal of Immunology, ji2100685 (2022)

Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells, Elsner, C.# , Ponnurangam, A.# , Kazmierski, J., Zillinger, T., Jansen, J., Todt, D., Döhner, K., Xu, S., Ducroux, A., Kriedemann, N., Malassa, A., Larsen, P.K., Hartmann, G., Barchet, W., Steinmann, E., Kalinke, U., Sodeik, B., Goffinet, C., Proceedings of the National Academy of Sciences, 117(32):19475 (2020)

cGAS-mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites, Xu, S.# , Ducroux, A.# , Ponnurangam, A., Franz, S., Vieyres, G., Müsken, M., Zillinger, T., Malassa, A., Ewald, E., Hornung, V., Barchet, W., Häussler, S., Pietschmann, T., Goffinet, C., Cell Host & Microbe, 20(4):443 (2016)