HTLV-1 intasome structural studies
EMSL Project ID
50990
Abstract
Integrase (IN) is an essential viral enzyme that catalyzes the integration of reverse-transcribed retroviral DNA into the host’s chromosome, and human immunodeficiency virus type-1 (HIV-1) IN is the target of several clinically used antiviral drugs (INSTI: IN strand-transfer inhibitors). IN oligomerizes with both ends of the linear viral DNA, forming a nucleoprotein complex (intasome) capable of capturing a target (cellular) DNA for concerted integration of both viral DNA termini. Recent structural studies have revealed unexpected diversity of intasome assemblies for four different genera of retroviruses, ranging from a tetrameric IN for spumavirus PFV, octameric IN for alpharetrovirus RSV and betaretrovirus MMTV, to a hexadecameric (16-mer) IN for a lentivirus MVV. Human T-lymphotropic virus type 1 (HTLV-1) is an important deltaretroviral human pathogen that causes Adult T-cell leukemia (ATL) and a neurological disorder, Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). However, the intasome structure for a deltaretrovirus has not been reported, which limits our understanding of HTLV-1 integration mechanisms. Using cryo-EM, we are pursuing structures of the HTLV-1 intasome to shed light on the conserved and unique features of deltaretroviral IN and to understand how INSTIs interact with the HTLV-1 IN active site. Detailed understanding of HTLV-1 integration mechanisms would facilitate development of antiviral strategies as well as novel gene delivery tools that achieve distinct integration profiles in human cells than the lentiviral vectors, which would potentially be useful in gene therapy.
Project Details
Start Date
2019-08-01
End Date
2020-01-14
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members