Interplay between innate cytokines in HIV-1 control

Project Overview

There remains an urgent need for effective prophylactic strategies to halt the spread of the HIV-1 pandemic. In addition, improved therapeutic strategies are required, both to provide more efficient long-term control of virus replication and to reduce the ongoing immune activation associated with chronic HIV-1 persistence in individuals on combination antiretroviral therapy. To inform the rational development of novel approaches to fill these needs, this project will address interactions between innate cytokines and the implications of this interplay for control of HIV-1 replication and immune activation.

Innate cytokines such as type I and type III interferons (IFNs) and members of the transforming growing factor (TGF) beta superfamily are highly pleiotropic, each binding to cell-surface receptors and triggering the upregulation of multiple genes whose roles include mediation of direct antiviral activity, immunoregulation, and modulation of cellular activation, proliferation and survival. Innate cytokines thus play both protective and pathogenic roles during HIV-1 infection, mediating antiviral activity but also promoting immune activation and virus dissemination (Borrow, Curr Opin HIV AIDS, 2011). For example, type I IFN production is rapidly upregulated in response to HIV-1 infection (Stacey et al 2009) and plays an important role in counteracting the establishment of infection and controlling subsequent virus replication (Fenton-May et al, 2013; Sandler et al 2014; Iyer et al PNAS 2018); but the immunoregulatory and pro-apoptotic effects of type I IFNs have also been implicated in driving sustained immune activation and contributing to lymphocyte depletion and HIV pathogenesis (Utay and Douek, 2016; Nganou-Makamdop et al, 2018).

Importantly, previous in vitro studies addressing the mechanisms by which innate cytokines impact on viral control have analysed them individually; but in vivo, cells are exposed simultaneously or serially to multiple innate cytokines, and also to other stimuli. Recent publications have highlighted the potential for cytokine exposure to modulate responses to other cellular stimuli not only through transcription-dependent mechanisms, but also through transcription-independent mechanisms that involve integration of signalling via different receptors to elicit a unique response profile (Bezbradica and Medzhitov, 2012; Sikorski et al 2011; Bezbradica et al 2014). Integration of signals received through diverse cell-surface receptors is poorly-understood, but is likely to have an important impact on the in vivo response to innate cytokines during HIV infection. For example, how does interplay between type I or III IFN and T cell receptor signalling during acute HIV-1 infection affect both the T cell response and control of HIV-1 replication in infected CD4 T cells; and how does exposure of macrophages to type I IFNs and/or TGFbeta together with elevated circulating LPS levels during chronic HIV-1 infection affect proinflammatory cytokine production and HIV-1 persistence in these cells? To address these and related questions, this project will employ systems biology approaches including a novel CyTOF-based method for analysing signalling pathways in distinct leukocyte subsets, single cell and bulk RNA sequencing methods, proteomic analyses, and high-dimensional flow cytometry-based dissection of T cell and macrophage responses will be employed, alongside recently-developed HIV-1 replication systems and more classical approaches.

References:

Bezbradica J.S. and R. Medzhitov. Integration of cytokine and heterologous receptor signalling pathways. Nat Immunol 10: 333-339, 2009.

Borrow P. Innate immunity in acute HIV-1 infection. Curr. Opin. HIV AIDS 6: 353-363, 2011.

Fenton-May A.E., O. Dibben, T. Emmerich, H. Ding, K. Pfafferott, M.M. Aasa-Chapman, P. Pellegrino, I. Williams, M.S. Cohen, F. Gao, G.M. Shaw, B.H. Hahn, C. Ochsenbauer, J.C. Kappes and P. Borrow. Relative resistance of HIV-1 founder viruses to control by interferon-alpha. Retrovirology, 10: 146, 2013.

Iyer S.S., F. Bibollet-Ruche, S. Sherrill-Mix, G.H Learn, L. Plenderleith, A.G. Smith, H.J. Barbian, R.M. Russell, M.V. Gondim, C.Y. Bahari, C.M. Shaw, Y. Li,
T. Decker, B.F. Haynes, G.M. Shaw, P.M. Sharp, P. Borrow and B.H. Hahn. Resistance to Type 1 Interferons is a Major Determinant of HIV-1 Transmission Fitness. PNAS, 114: E590-E599, 2017.

Nganou-Makamdop K., Billingsley JM, Yaffe Z, O'Connor G, Tharp GK, Ransier A, Laboune F, Matus-Nicodemos R, Lerner A, Gharu L, Robertson JM, Ford ML, Schlapschy M, Kuhn N, Lensch A, Lifson J, Nason M, Skerra A, Schreiber G, Bosinger SE and Douek DC.Type I IFN signaling blockade by a PASylated antagonist during chronic SIV infection suppresses specific inflammatory pathways but does not alter T cell activation or virus replication. PloS Pathog 14: e1007246, 2018.

Sandler N.G., Bosinger SE, Estes JD, Zhu RT, Tharp GK, Boritz E, Levin D, Wijeyesinghe S, Makamdop KN, del Prete GQ, Hill BJ, Timmer JK, Reiss E, Yarden G, Darko S, Contijoch E, Todd JP, Silvestri G, Nason M, Norgren RB Jr, Keele BF, Rao S, Langer JA, Lifson JD, Schreiber G and Douek DC. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511:601-5, 2014.

Sikorski, K.. Czerwoniec A, Bujnicki JM, Wesoly J and Bluyssen HA. STAT1 as a novel therapeutical target in pro-atherogenic signal integration of IFNγ, TLR4 and IL-6 in vascular disease. Cytokine Growth Factor Rev. 22:211-9, 2011.

Stacey, A.R., P. Norris, L. Qin, E.A. Haygreen, E. Taylor, J. Heitman, M. Lebedeva, A. DeCamp, D. Li, D. Grove, S.G. Self and P. Borrow. Induction of a striking systemic cytokine cascade prior to peak viraemia in acute human immunodeficiency virus infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J. Virol. 83: 3719-3733, 2009. 

Utay N.S. and D.C. Douek. Interferons and HIV Infection: The Good, the Bad, and the Ugly. Pathog Immun. 1:107-116, 2016.

 

 

Training Opportunities

This is a cross-disciplinary project that will employ a range of cutting-edge molecular, cellular, immunological and virological techniques.  There will be the opportunity to gain expertise in methods including CyTOF and high-dimensional flow cytometry analysis techniques, bulk RNASeq and single-cell gene expression profiling using 10X platforms; qRT-PCR, mass spectrometry and Western blot based protein profiling; a breadth of immunoassays and virological techniques including the generation and modification of infectious molecular clones of HIV, and methods for quantifying virus replication and analysing blocks to replication; and gene knockdown by siRNA inhibition and CRISPR-Cas approaches.

The successful candidate will be offered basic training in bioinformatics and will contribute to analysis of the large datasets generated. More generic research training, e.g. in experimental design, data interpretation, statistical analysis and presentation and writing skills will also be provided. The student will form part of a group involved in active collaborations with multiple international HIV research teams, and they will have the opportunity to attend and present their data at internal, national and international meetings. The successful candidate will be based in the NMD Research Building in Prof. Borrow’s group, with close interactions with Dr. Rehwinkel’s lab in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine. We offer access to state-of-the-art facilities. The successful candidate will be co-supervised by Persephone Borrow and Jan Rehwinkel and additional day-to-day supervision will be provided by experienced members of both labs.

 

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 1018

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Persephone Borrow NDM Research Building Oxford University, NDM Research Building GBR persephone.borrow@ndm.ox.ac.uk
Prof Jan Rehwinkel Investigative Medicine Division Oxford University, Weatherall Institute of Molecular Medicine GBR jan.rehwinkel@imm.ox.ac.uk

There are no publications listed for this DPhil project.