NIH grant: Defining Nuclear Pore Complex Subsets and Import Pathways that Regulate the Fate of HIV-1 Integration and Gene Expression (1R01AI200600-01)

retained text

NIH grant 1R01AI200600-01: Defining Nuclear Pore Complex Subsets and Import Pathways that Regulate the Fate of HIV-1 Integration and Gene Expression
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Adarsh  Dharan. Award: $617374.
Start: 2026-08-07T00:00:00.
Abstract
A hallmark feature of HIV-1 infection is their ability to infect non-dividing cells and gain access to the nucleus
through the nuclear pore complex (NPC). While extensive work has focused on viral determinants of nuclear
entry, particularly capsid elasticity and remodeling, much less is known about how virus infection alters NPC
architecture and auxiliary factors to regulate nuclear entry and intranuclear viral events. Our preliminary studies
reveal that HIV-1 infection induces nucleoporin relocalization, altering NPC permeability, and triggering turnover
of NPC auxiliary factors such as FXR1 and UBAP2L potentially to remodel NPCs during nuclear entry,
Furthermore, we demonstrate that forcing HIV-1 through alternate nuclear import pathways redirects integration
into repressive chromatin and promotes a transcriptionally silent state. These findings suggest that HIV-1 nuclear
entry exploits specific NPC subsets and host regulators to dictate downstream nuclear events. This proposal will
define the molecular composition and remodeling of NPC subsets engaged by HIV-1 (Aim 1), determine how
distinct nuclear import routes influence productive versus latent infection in CD4⁺ T cells and macrophages (Aim
2), and characterize how nuclear entry pathways dictates the epigenetic landscape encountered in the nucleus
(Aim 3). To achieve this, we will employ innovative tools including our unique chemically induced NPC blockades,
degron mediated acute depletion of nucleoporins, CRISPR based editing and chromatin profiling approaches
(ChIP-seq and integration site mapping). By elucidating how HIV-1 exploits NPC remodeling and import pathway
selection to shape infection outcomes, this project aims to characterize host virus interactions at the nuclear
envelope and reveal new targets for therapeutic strategies aimed at blocking infection or selectively reactivating
latent reservoirs.

document fetched 2026-08-16 06:34