# Functionally Defining HIV-Host Interactions During the Early HIV-1 Lifecycle

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $1,355,103

## Abstract

ABSTRACT: The early phase of the HIV lifecycle encompasses the steps from virus fusion to provirus integration
and represents a critical therapeutic target. Small molecule inhibitors of HIV encoded reverse transcriptase and
integrase are central components of many therapeutic treatment regimens and pre-exposure prophylaxis.
Despite the therapeutic importance of these steps, the field still lacks consensus on several outstanding
questions including how trafficking and uncoating are linked to reverse transcription, how and in what state the
provirus transits through the nuclear pore, what host factors are involved in these processes, and what
distinguishes between a virus that will establish successful infection and one that will fail. Due to the inefficient
and relatively stochastic nature of early phase replication, only a small percentage (~15%) of particles that enter
the cytoplasm after fusion will result in successful provirus integration. As a result, population-based assays that
measure what most viruses do may or may not actually capture what successful viruses do. Nevertheless,
technical limitations have historically mandated a reliance on population-based assays, immortalized cell line
models, and indirect measurements of biological processes whose underlying assumptions don’t necessarily
reflect the biological priors. Only recently have innovations in single-particle tracking, molecular imaging, gene
editing, and structural determination allowed for researchers to overcome these limitations, but these specialized
technologies have not yet been brought together to answer these critical questions in HIV biology. Here, we
assemble a team of HIV researchers with complementary expertise in these powerful approaches to dissect and
define the interactions, kinetics, and dynamics between fusion and integration that result in productive infection.
We propose to leverage a newly optimized toolbox of molecular labeling methods, a technique collectively
termed Infectious Virion Tracking (IVT), to image and track the behavior of individual viral components, ultimately
separating individual virions that result in successful infection from those that enter the cell non-productively.
Additional specialized technologies including primary cell CRISPR-Cas9 gene editing and cryogenic electron
microscopy will be leveraged to interrogate the structure and function of individual components along the route
to productive infection. Wielding this novel and innovative series of tools, approaches, and equipment, we aim
to: 1) Define the infectious pathway of HIV from fusion to integration in optimized cell culture models and primary
human target cells; 2) Determine the role of host permissivity factors and viral components in the processes of
the early phase of the HIV life-cycle; and 3) Visualize and define the structure of the viral based machines
associated with the HIV genome as it progresses through reverse transcription, traffics through the cytoplasm,
enter...

## Key facts

- **NIH application ID:** 10359682
- **Project number:** 5R01AI150998-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Paul D. Bieniasz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,355,103
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359682

## Citation

> US National Institutes of Health, RePORTER application 10359682, Functionally Defining HIV-Host Interactions During the Early HIV-1 Lifecycle (5R01AI150998-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10359682. Licensed CC0.

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