# Role of Vpu, Tetherin, and Siglec-1 in HIV-1 Replication

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $408,407

## Abstract

Project Summary
Vpu enhances retrovirus particle release from the plasma membrane by inhibiting the
potent cellular restriction factor BST2/tetherin. It has become clear that cellular trafficking
pathways are the key to understanding the interplay between tetherin and Vpu. We have
uncovered two major clues that to tetherin trafficking and Vpu action that form the basis
for the first two Aims of this project. We have also found that tetherin contributes in a
unique way to HIV replication in human macrophages, influencing the formation of the
virus-containing compartment (VCC). The overall goals of this project are to define the
mechanism of restriction of particle release by tetherin and the mechanism by which Vpu
overcomes restriction through defining their interactions in the endosomal recycling
complex (ERC). The first new discovery is that tetherin traffics throught the ERC, and
can be quantitatively trapped in this compartment. Experiments in Aim 1 will define the
Rab and Rab-related factors that specifically sort tetherin to the site of assembly and
restriction on the plasma membrane, and will define a model for Vpu action that requires
disruption of ERC trafficking. Experiments in Aim 2 follow up on a surprising finding that
tetherin can rescue HIV-1 envelope onto matrix-mutant HIV particles that normally lack
envelope, even restoring their infectivity. Defining the mechanism will uncover important
facets of tetherin trafficking, including how the natural isoforms of tetherin differ in
specifics of trafficking. Aim 3 will follow up on our discovery that tetherin is an important
determinant of VCC formation, and focuses on the role of Siglec-1 and the role it plays in
VCC formation and cell-cell transmission. Together these studies will continue a
productive line of investigation into tetherin and Vpu biology and HIV replication in
macrophages, and will facilitate new antiviral approaches and HIV cure strategies.

## Key facts

- **NIH application ID:** 9983567
- **Project number:** 5R01AI150475-13
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** PAUL W. SPEARMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,407
- **Award type:** 5
- **Project period:** 2003-12-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983567

## Citation

> US National Institutes of Health, RePORTER application 9983567, Role of Vpu, Tetherin, and Siglec-1 in HIV-1 Replication (5R01AI150475-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983567. Licensed CC0.

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