# Molecular Interactions of HIV-1 with the Nuclear Pore Complex

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $1,369,167

## Abstract

HIV-1 enters the nucleus of non-dividing cells where the reverse transcribed viral DNA is
integrated into the host genome. Whereas the nuclear pore complex (NPC) prevents passive
transport of large macromolecules, HIV-1 has evolved effective strategies to penetrate this barrier.
The HIV-1 nuclear import is a poorly understood process that involves complex interactions with
the nuclear import machinery, including several nucleoporins, transportin-3, and CPSF6, all of
which bind the viral capsid core, which comprises hundreds of copies of the capsid protein (CA).
Pleiotropic effects caused by nucleoporin knockdown and the ability of HIV-1 to use alternative
import pathways have impeded the mechanistic studies of nuclear import and frustrated efforts to
identify the full array of host factors involved in this process. Our single particle tracking
experiments revealed that HIV-1 infection progresses through CA-dependent docking at the
nuclear membrane, followed by uncoating (loss of CA) and CA-dependent nuclear transport to
the sites of integration. However, very little is known regarding the molecular details and dynamics
of virus-NPC interactions, including the structural changes in the architecture of both HIV-1 and
the NPC in the course of nuclear import. There is thus an unmet need for structural and functional
studies on the molecular mechanisms of HIV-1 nuclear import in the context of productive
infection. We propose to combine cutting-edge approaches developed by our highly collaborative
team to delineate the molecular interactions and structural changes in the virus and NPC during
the nuclear import. Specifically, we will: (1) identify the host factors involved in HIV-1 import using
novel proteomics and chemical cross-linking approaches; (2) obtain cryo-electron tomography
(cryo-ET) and cross-linking mass-spec structures of the HIV-1 core/NPC complexes by capturing
the incoming virus through our new on-demand pore clogging assay; and (3) develop correlative
fluorescence/cryo-ET imaging pipeline to structurally characterize the intermediates of HIV-1
nuclear import. Knowledge of molecular interactions during the HIV-1 nuclear import should help
identify novel therapeutic targets to block infection, provide a framework for studies of the nuclear
import of other viruses and further fundamental understanding of the nuclear pore function.

## Key facts

- **NIH application ID:** 10241258
- **Project number:** 5R01AI148382-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Gregory B Melikian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,369,167
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241258

## Citation

> US National Institutes of Health, RePORTER application 10241258, Molecular Interactions of HIV-1 with the Nuclear Pore Complex (5R01AI148382-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241258. Licensed CC0.

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