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DTSTAMP:20261022T105718Z
UID:1793881800@ist.ac.at
DTSTART:20261105T133000
DTEND:20261105T143000
DESCRIPTION:Speaker: Mathias Percipalle\nhosted by Amelia Douglass\nAbstrac
 t: The Human T-Cell Leukemia virus type 1 (HTLV-1) is an oncogenic deltare
 trovirus infecting at least 5-10 million people worldwide. It is the causa
 tive agent of HTLV-1 associated myelopathy/tropical spastic paraparesis (H
 AM/TSP)\, a spinal cord disease\, and adult T-cell leukemia/lymphoma (ATLL
 )\, a severe T-cell malignancy. No therapies target HTLV-1 infection\, and
  many steps of its late-stage viral life cycle remain poorly understood. T
 his thesis structurally dissects two linked stages of this cycle: the dive
 rgent immature assembly of HTLV-1\, and its ability to induce an extracell
 ular-matrix like structure on infected cells\, termed a viral biofilm. Re
 troviral capsid (CA) proteins display a conserved two-domain architecture 
 consisting of independently folded N-terminal (CA-NTD) and a C-terminal (C
 A-CTD) subdomains. Yet\, different retrovirus species employ remarkably va
 riable geometrical solutions to stabilize the CA lattices forming the imma
 ture virus particle. HTLV-1 relies on the CA-NTD to stabilize its immature
  lattice\, while the Human Immunodeficiency virus type 1 (HIV-1) relies on
  a contiguous structural unit formed by the CA-CTD and the spacer peptide 
 1 (SP1). This raises the question of whether immature assembly phenotypes 
 are modular features encoded independently within individual CA subdomains
 \, or emergent features requiring strict co-evolution of both subdomains. 
 To test this\, we designed chimeric proteins pairing the CA subdomains of 
 HTLV-1 and HIV-1. Our results show that pairing assembly-driving subdomain
 s from the two species still allows them to independently form their nativ
 e immature contacts\, while attempting to impose their preferred curvature
  on each other. Mutations of either chimeric subdomain do not disrupt asse
 mbly\, but rather shift the phenotype balance while relieving curvature st
 rains\, demonstrating that immature assembly properties can be encoded int
 o a single subdomain. The two-domain architecture of retroviral capsids th
 us reflects a division of labor built on structural modularity\, where one
  subdomain is the key driver for assembly competence while the other could
  serve more regulatory functions.Once assembled and released\, HTLV-1 part
 icles accumulate at the cell surface within a viral biofilm\, a structure 
 unique among retroviruses that strongly enhances cell-to-cell transmission
 . However\, the biofilm architecture and virion organization within it\, a
 nd their influence on virus infectivity\, have not been explored. Using cr
 yo-electron microscopy methods on purified HTLV-1 biofilm\, we revealed an
  extracellular environment enriched in virions\, membranous vesicles and m
 atrix components. Biofilm-embedded virions display large heterogeneity in 
 size and core morphology\, including single and double cores and putative 
 maturation intermediates. Strikingly\, virions are frequently clustered an
 d tethered to each other and to surrounding membranes by thin linear densi
 ties whose dimensions match the host restriction factor tetherin\, suggest
 ing that HTLV-1 may exploit a canonical restriction factor to retain virio
 ns within the biofilm. We also determined the mature HTLV-1 capsid lattice
  structure to 9.4 Å resolution from biofilm-embedded particles with canon
 ical cores. The structure reveals that HTLV-1 still converges onto the mat
 ure fold conserved across retroviruses\, despite having a divergent immatu
 re assembly mechanism\, and seemingly undergoes a less dramatic maturation
  than other retroviruses. Together\, these results expand the structural 
 framework for how HTLV-1 assembles\, matures and organizes itself at the i
 nfected cell surface.
LOCATION:Sunstone Bldg / Ground floor / Big Seminar Room B (I23.EG.102) and
  Zoom\, ISTA
ORGANIZER:
SUMMARY:Mathias Percipalle: Thesis Defense: Structurally dissecting the lat
 e-stage viral lifecycle of the Human T-Cell Leukemia Virus Type 1
URL:https://talks-calendar.ista.ac.at/events/6715
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