# Affinity Gradient-Based Transport of HIV Capsid Cores through the Nuclear Pore Complex

> **NIH NIH R21** · EMORY UNIVERSITY · 2023 · $234,750

## Abstract

Affinity Gradient-Based Transport of HIV Capsid Cores Through the Nuclear Pore Complex:
Project Summary
Lentiviruses such as human immunodeficiency virus type 1 (HIV-1) have evolved strategies to enter the nucleus
of non-dividing cells and integrate their reverse transcribed DNA into host genomes. There are several reports
on the transport of HIV-1 complexes to, and import through, the Nuclear Pore Complex (NPC), a massive
channel in the nuclear envelope composed of multiple copies of ~30 nucleoporins (NUPs). Recent data
suggests that the supramolecular fullerene cone-shaped viral capsid (CA) core (~120x50 nm) that
encapsulates the viral genome can penetrate the central channel (diameter of ~60 nm) of the NPC, at least
partially, intact. It is widely accepted that at least a subset of NUPs interacts with the HIV-1 CA proteins of the
viral core through their phenylalanine-glycine (FG) motifs. However, the molecular mechanisms by which a
largely intact HIV-1 capsid passes through the NPC – a defining feature of lentiviruses – remains to be
elucidated.
Mechanistic studies of HIV-1 nuclear entry have been stymied primarily by the inherent complexity of the system.
The NPC is one of the largest assemblies in the Eukaryotic cell (~120 MDa) and HIV-1 capsid core is one of the
largest cargoes delivered to the cell nucleus. Based on analysis of state-of-the-art published data and pilot
results, we propose a paradigm-shifting hypothesis that addresses the mechanism of transport of HIV-1
capsid core through the NPC and challenges the generalized view on nucleo-cytoplasmic transport. We
propose that HIV-1 capsid core is a complex transport receptor that is translocated via an opportunistic affinity
gradient within the NPC. The affinity gradient consists of various “signatures” on specific nucleoporins
that are naturally distributed along the nucleo-cytoplasmic axis of the NPC. The subset of such
“signatures” involves various flavors of FG motifs that are segregated in the NPC to distinct zones. We will use
our multidisciplinary expertise, armamentarium of techniques, and preliminary data, to address the following
specific aims: 1. Determine the structures of complexes of CA proteins with peptides of different FG motifs. 2.
Biochemically and biophysically characterize the interactions between CA and various FG peptides. 3.
Discriminate between various flavors of FG motif interactions with mutant capsid cores using nuclear import
experiments. The scientific premise is that combined structural, biochemical, biophysical and imaging
approaches will provide important mechanistic insight into interactions of HIV-1 capsid core complexes with
NPC constituents and reveal the capsid core – NPC structural intermediates of translocation. Knowledge of
the molecular interactions during HIV-1 nuclear import will shed light on the strategy HIV-1 deploys to deliver
its genome to the nucleus; our fundamental understanding of NPC function; provide a framework for studies of
the...

## Key facts

- **NIH application ID:** 10700524
- **Project number:** 1R21AI176946-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ivo Melcak
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $234,750
- **Award type:** 1
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700524

## Citation

> US National Institutes of Health, RePORTER application 10700524, Affinity Gradient-Based Transport of HIV Capsid Cores through the Nuclear Pore Complex (1R21AI176946-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10700524. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*