Dr Clare Jolly
UNAIDS estimates around 33 million people are living with HIV/AIDS and approximately 25 million have died. While the ultimate goal remains the development of an effective HIV-1 vaccine, there is also a need for new and improved anti-viral strategies and this requires a better understanding of the molecular cell biology and pathogenesis of HIV-1 infection.
The research interests of my laboratory are broadly aimed at understanding how HIV-1 assembles in and disseminates between CD4 T cells - the main targets for HIV-1 infection in vivo.
Cell-cell spread at Virological Synapses
Previous work by us and others have shown that direct cell-cell spread of HIV-1 between T cells is a very efficient mode of viral dissemination. Cell-cell spread of HIV-1 takes place across a virus-induced multimolecular structure called the virological synapse (VS)(see publications). Our identification of the HIV-1 T cell VS provided a molecular framework to explain how cell-cell spread of HIV-1 occurs and why it so efficient. The VS is characterised by cytoskeleton-driven recruitment of viral proteins, adhesion molecules and entry receptors (CD4 and chemokine receptors) to the site of contact between an HIV-1-infected T cell and a susceptible target T cell. This promotes rapid infection of the target cell by focussing virus assembly and budding to the site of cell-cell contact. Increasing evidence shows that cell-cell confers a number of replicative advantages to the virus, including more efficient spread and may allow HIV-1 to evade aspects of the humoral immune response, innate antiviral restriction factors and antiretroviral drugs. Thus cell-cell spread at VS may pose a considerable barrier to HIV-1 eradication from the host. The VS shares many similarities with a well-described structure called the immunological synapse (IS) and we hypothesise that HIV-1 spread at the VS may involve related cellular machinery, and that HIV-1 hijacks elements of the regulated secretory pathway to transport viral proteins and coordinate assembly and egress. Our current research is focussed on delineating the contribution of T cell trafficking pathways and associated molecules to HIV-1 pathogenesis in T cells. We are also seeking to identify cellular proteins that regulate VS formation and to delineate how they contribute to HIV-1 replication and spread.
The cell biology of HIV-1 replication
Virus assembly is a complex series of well-orchestrated events, in which all components must be delivered to the appropriate cellular location in a temporally and spatially controlled way. We are interested in determining how the viral envelope glycoprotein (Env) and the major structural protein Gag are trafficked to sites of HIV-1 assembly in T cells during both cell-free and cell-cell spread. We are particularly interested in the trafficking of Env and its incorporation into virions because of the essential role Env plays in viral infectivity, tropism and VS formation.
Cell biology of HIV replication and spread
Regulation of virological synapses
I lecture on the Molecular Virology course and MSc programs.
Dr Elisabetta Groppelli
- Titanji BK, Aasa-Chapman M, Pillay D, Jolly C (2013). Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells. Retrovirology, 10(1), 161 - 161. doi:10.1186/1742-4690-10-161
- Wei B, Han L, Abbink TE, Groppelli E, Lim D, Thaker YR, Gao W, Zhai R, Wang J, Lever A, Jolly C, Wang H, Rudd CE (2013). Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors. Retrovirology, 10(1), 101 - 101. doi:10.1186/1742-4690-10-101
- Zhou L, Sokolskaja E, Jolly C, James W, Cowley SA, Fassati A (2011). Transportin 3 promotes a nuclear maturation step required for efficient HIV-1 integration.. PLoS Pathog, 7(8), e1002194 - . doi:10.1371/journal.ppat.1002194
- JOLLY C (2011). Cell-to-cell transmission of retroviruses: Innate immunity and interferon-induced restriction factors. Virology, 411(2), 251 - 259. doi:10.1016/j.virol.2010.12.031
- Jolly CL, Welsch S, Michor S, Sattentau QJ (2011). The Regulated Secretory Pathway in CD4+ T cells Contributes to Human Immunodeficiency Virus Type-1 Cell-to-Cell Spread at the Virological Synapse. PLoS Pathogens, 7, e10022226 - . doi:10.1371/journal.ppat.1002226
- Martin N, Welsch S, Jolly C, Briggs JA, Vaux D, Sattentau QJ (2010). Virological synapse-mediated spread of human immunodeficiency virus type 1 between T cells is sensitive to entry inhibition. Journal of Virology, 84(7), 3516 - 3527. doi:10.1128/JVI.02651-09.
- Jolly C (2010). T Cell Polarization at the Virological Synapse. Viruses, 2(6), 1261 - 1278. doi:10.3390/v2061261
- Gonzales N, Bermejo M, Calonge E, Jolly C, Arenzena-Seisdedos F, Pablos JL, Sattentau QJ, Alcami J (2010). SDF-1/CXCL12 production by mature dendritic cells inhibits the propagation of X4-tropic HIV-1 isolates at the dendritic cell-T-cell infectious synapse. Journal of Virology, 84(9), 4341 - 4351.
- Jolly C, Booth NJ, Neil SJ (2010). Cell-Cell spread of Human Immunudeficiency Virus Type 1 overcomes tetherin/BST-2-mediated restriction in T cells. Journal of Virology, 84(23), 12185 - 12199. doi:10.1128/JVI.01447-10
- Martin N, Welsch S, Jolly C, Briggs JAG, Vaux D, Sattentau QJ (2010). Virological Synapse-Mediated Spread of Human Immunodeficiency Virus Type 1 between T Cells Is Sensitive to Entry Inhibition. JOURNAL OF VIROLOGY, 84(7), 3516 - 3527. doi:10.1128/JVI.02651-09
- Sowinski S, Alakoskela JM, Jolly C, Davis DM (2010). Optimized methods for imaging membrane nanotubes between T cells and trafficking of HIV-1.. Methods, , - .
- Jolly C, Sattentau QJ (2010). Attachment factors. In Pohlmann S, Simmons G (Ed.), Virus Entry into Host Cells (pp. - ). : Landes Bioscience.
- Sowinski S, Jolly C, Berninghausen O, Purboo MA, Chauveau A, Kohler K, Oddos S, Eissmann P, Brodsky FM, Hopkins C, Onfelt B, Sattentau Q, Davis DM (2008). Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nature Cell Biology, 10(2), 211 - 219. doi:10.1038/ncb1682
- Jolly C, Sattentau QJ (2007). Regulated secretion from CD4+ T cells. Trends in Immunology, 28(11), 474 - 481. doi:10.1016/j.it.2007.08.008
- Jolly C, Sattentau QJ (2007). Human immunodeficiency virus type 1 assembly, budding, and cell-cell spread in T cells take place in tetraspanin-enriched plasma membrane domains. Journal of Virology, 81(15), 7873-7884 - . doi:10.1128/JVI.01845-06
- Jolly C, Mitar I, Sattentau QJ (2007). Adhesion molecule interactions facilitate human immunodeficiency virus type 1-induced virological synapse formation between T cells. Journal of Virology, 81(24), 13916-21 - . doi:10.1128/JVI.01585-07
- Jolly C, Mitar I, Sattentau QJ (2007). Requirement for an intact T-cell actin and tubulin cytoskeleton for efficient assembly and spread of human immunodeficiency virus type 1. Journal of Virology, 81(11), 5547-5560 - . doi:10.1128/JVI.01469-06.
- Jolly C, Sattentau QJ (2005). Human immunodeficiency virus type 1 virological synapse formation in T cells requires lipid raft integrity. Journal of Virology, 79(18), 12088 - 12094. doi:10.1128/JVI.79.18.12088-12094.2005.
- Jolly C, Sattentau QJ (2004). Retroviral spread by induction of virological synapses. Traffic, 5(9), 643 - 650. doi:10.1111/j.1600-0854.2004.00209.x
- Jolly C, Kashefi K, Hollinshead M, Sattentau QJ (2004). HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. Journal of Experimental Medicine, 199(2), 283 - 293. doi:10.1084/jem.20030648.
- Fazli A, Bradley SJ, Kiefel MJ, Jolly C, Holmes IH, von Itzstein M (2001). Synthesis and biological evaluation of sialylmimetics as rotavirus inhibitors. Journal of Medicinal Chemistry, 44(20), 3292 - 3301. doi:10.1021/jm0100887
- Jolly C, Beisner BM, Ozser E, Holmes IH (2001). Non-lytic extraction and characterisation of receptors for multiple strains of rotavirus. Archives of Virology, 146(7), 1307 - 1323. doi:10.1007/s007050170093
- Jolly C, Huang JA, Holmes IH (2001). Selection of rotavirus VP4 cell receptor binding domains for MA104 cells using a phage display library. Journal of Virological Methods, 98(1), 41 - 51. doi:10.1016/S0166-0934(01)00357-3
- Jolly C, Beisner BM, Holmes IH (2000). Rotavirus infection of MA104 cells is inhibited by Ricinus lectin and separately expressed single binding domains. Virology, 275(1), 89 - 97. doi:10.1006/viro.2000.0470