> Back to seminars list

Seminar

Monday, May 13th, 2019
11h30
Centre de Recherche - Paris - Amphith√©√Ętre Marie Curie

Catch me if you can: HIV Capsid and evasion of innate immunity is associated with human pandemicity

Like all viruses, lentiviruses must navigate the hostile environment of the host cell in order to infect, produce new viral particles, and transmit to new cells. A principal component of cellular defences is detection or sensing of incoming viruses and subsequent production of inflammatory cytokines, particularly type 1 interferons. It is likely that all viral infections trigger interferons in vivo and the degree to which they do this, and their capacity to suppress interferons and their effects, are key to determining transmission efficiency, host range and disease pathogenesis. Lentiviruses combine evasion with direct antagonism of specific proteins or pathways that would otherwise suppress infection. Despite twelve documented lentiviral zoonoses from simians to humans, only one pandemic human lentivirus exists. We have studied the role of the HIV capsid in evasion of innate immune sensing and compared pandemic and non-pandemic isolates. We find that pandemic HIV-1(M) uniquely encloses viral DNA within intact viral capsids to cloak it from innate immune DNA sensors. We find that only pandemic HIV has evolved to regulate capsid behaviour allowing replication in myeloid cells. We speculate that these adaptations have contributed to pandemic human-to-human sexual transmission. This talk will discuss our data and their implications for understanding the biology of innate immune sensing and lentiviruses and their pathogenesis and zoonotic potential.

5 publications:

Fletcher AJ, Vaysburd M, Maslen S, Zeng J, Skehel JM, Towers GJ, James LC. 2018 Trivalent RING Assembly on Retroviral Capsids Activates TRIM5 Ubiquitination and Innate Immune Signaling. Cell Host Microbe. Dec 12;24(6):761-775.e6.

Mlcochova P, Caswell SJ, Taylor IA, Towers GJ, Gupta RK. 2018. DNA damage induced by topoisomerase inhibitors activates SAMHD1 and blocks HIV-1 infection of macrophages. EMBO J. 37:50-62.

Jacques DA, McEwan WA, Hilditch L, Price AJ, Towers GJ, James LC. 2016. HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature. 536: 349-53.

Fletcher AJ, Christensen DE, Nelson C, Tan CP, Schaller T, Lehner PJ, Sundquist WI, Towers GJ. 2015
TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription.
EMBO J. 34: 2078-95

Rasaiyaah, J., C. P. Tan, A. J. Fletcher, A. J. Price, C. Blondeau, L. Hilditch, D. A. Jacques, D. L. Selwood, L. C. James, M. Noursadeghi and G. J. Towers. 2013. HIV-1 evades innate immune recognition through specific co-factor recruitment. Nature. 503: 402-5

 

Speaker(s)

Prof. Greg Towers

University College London - Division of Infection and Immunity, London UK

Invited by

Nicolas Manel
Domain 3 - U932 - Immunity and Cancer

Institut Curie

Philippe Benaroch
Domain 3 - U932 - Immunity and Cancer

Institut Curie

Contact

Elodie Mieville

Send an e-mail

Learn more

During my PhD (1991-95) I studied HIV-1 transcription at the Institute of Cancer Research with Mary Collins
(ICR) and David Latchman (UCL). (1995-98) I was a Post Doc at the National Institute of Medical Research
with Jonathan Stoye where we cloned Fv1, the first intracellular anti-retroviral restriction factor. I moved to
the Genethon gene therapy institute in France in 1998 to study how intracellular innate immunity impacts
gene therapy vector tropism. I joined UCL in 2000 and have been funded by Wellcome Trust fellowships
since 2002. I was awarded a chair at UCL in Molecular Virology in 2006. My research is funded by a
Wellcome Trust Senior Fellowship and a Wellcome Trust Collaborator Award. Research goals are to
understand how lentiviruses, such as HIV-1, infect cells, despite the highly evolved defensive intracellular
innate immune system. We aim to use this knowledge to design novel therapeutics, improve the use of
lentiviruses for gene therapy and to understand cell and viral biology and their evolution.