# Delineating HIV-1 nuclear import mechanisms through capsid interaction with MxB and the nuclear pore complex

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

ABSTRACT
Human Immunodeficiency Virus 1 (HIV-1) causes life-long infection, which requires taking antiviral drugs to
control the infection. No vaccines are available against this virus. The HIV-1 cone-shaped capsid core, made up
of capsid protein (CA), protects the HIV-1 genome, plays a major role in HIV-1 infection and interacts with several
host factors involved in nuclear import of viral complexes and integration into the host genome. The myxovirus
resistance protein B (MxB) is thought to restrict HIV-1 infection by inhibiting uncoating and blocking nuclear entry,
the latter measure by 2-Long Terminal Repeats (2-LTR) circles inside the nucleus. However, MxB does not
inhibit the appearance of CA inside the nucleus of infected cells, even when infection is inhibited. Additionally,
measuring 2-LTR circles in the nucleus, which is a marker for HIV-1 nuclear import, does not correlate with
productive infection. Currently, little is known about the kinetics and sites of HIV-1 uncoating and the role of MxB
in regulating this process. HIV-1 nuclear import is also not completely understood. Several nucleoporins (NUPs),
which form the nuclear pore complex (NPC), interact with CA to promote HIV-1 nuclear import. The NPC was
previously thought to be a static structure with an inner diameter of ~40nm, too small to allow nuclear import of
the 60nm-wide HIV-1 capsid core, leading to an assumption that HIV-1 has to uncoat before entering the nucleus.
However, recent evidence suggests that NPC is a dynamic structure that may expand and that HIV-1 cone-
shaped cores can enter the nucleus. Little is known about how the NPC and MxB interactions with HIV-1 CA
respectively promote or inhibit HIV-1 infection. Therefore, I hypothesize that the NPC-associated MxB blocks
nuclear import by inhibiting uncoating and that the nuclear import of HIV-1 core requires expansion of
the nuclear pore complex. In the two Specific Aims of this proposal, I will investigate the HIV-1 nuclear import
and CA core disassembly in the presence of MxB (Aim 1) and delineate the changes in nuclear pore architecture
caused by HIV-1 (Aim 2) using advance microscopy techniques. In Aim 1, I will determine HIV-1 nuclear entry
inhibition by MxB through visualizing the presence of fluorescently labeled integrase-superfolderGFP (INsfGFP)
inside the nucleus. I will also examine HIV-1 uncoating by visualizing loss of a fluorescently labeled cyclophilin
A derivative, which binds to CA with high avidity. In Aim 2, I will examine changes in the nuclear pore size upon
HIV-1 infection using super-resolution microscopy. I will infect NUP-labeled cells with HIV-1 CA mutant, which
fails to transport to the nucleoplasm and remains associated with NPC. I will then visualize the NPC with
Stimulated Emission Depletion (STED) microscopy and Stochastic Optical Reconstruction Microscopy
(STORM). This project will provide me with diverse training in virology, cell biology and advanced microscopy
techniques and will adv...

## Key facts

- **NIH application ID:** 10548633
- **Project number:** 1F31AI167527-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Dariana Torres Rivera
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548633

## Citation

> US National Institutes of Health, RePORTER application 10548633, Delineating HIV-1 nuclear import mechanisms through capsid interaction with MxB and the nuclear pore complex (1F31AI167527-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10548633. Licensed CC0.

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