# Mechanistic investigations of HIV restriction by Serincs

> **NIH NIH F30** · UNIVERSITY OF VIRGINIA · 2021 · $51,036

## Abstract

PROJECT SUMMARY: The placenta forms a physical barrier to HIV transmission by
separating maternal and fetal blood and a functional barrier by expressing a plethora of
restriction factors to inhibit viral replication. However, vertical transmission of HIV does occur
in utero and shows that these defenses are imperfect. This is consistent with the recently
described viral restriction factor, Serinc, which is highly expressed in the placenta and can
incorporate into budding viral particles to inhibit their ability to infect. However, Serinc is an
imperfect restriction factor as it is inactivated by the viral accessory protein, Nef, and some
sequences of the HIV surface protein, Env. We plan to study the mechanism of how Serinc
restricts HIV infection to gain a better understanding of host-pathogen interactions
occurring in the placenta and with the hope of enabling the development of novel anti-
virals that can exploit the same viral weakness as Serinc but are not susceptible to the same
pitfalls.
 Serincs are a family of 5 human plasma membrane proteins expressed in select tissues. Isoforms
Serinc3 and Serinc5 restrict HIV proliferation while Serinc2 incorporates into viral particles but does not
restrict. The exact mechanism by which Serinc3 and 5 reduce infectivity is incompletely understood but is
known to block infection at a step before cell entry. Two major theories have emerged: 1) Serinc
inactivates Env by causing changes to the conformation and distribution of Env trimers in the viral
particle or 2) Serinc slows or disrupts membrane fusion of the virus with the host cell plasma membrane.
In this study, we will take advantage of the development of plasma membrane “blebs” as a model for viral
membrane fusion to test the relative merits of two proposed mechanisms of Serinc. We will assess Serinc-
containing or -lacking HIV pseudoviruses for changes in structure and distribution of Env by cryo-
electron tomography and subtomogram averaging (aim 1). We will also assess whether Serincs block
membrane fusion by observing HIV pseudoviruses containing or lacking Serincs as they fuse to bleb
model membranes with high resolution cryo-electron tomography snapshots (aim 2.1) and higher
throughput fluorescence microscopy single-particle viral fusion assays (aim 2.2). Preliminary results
show Serinc3 and Serinc5 block membrane fusion by disrupting fusion pore opening but do not affect
Env distribution or the speed at which viral particles undergo membrane fusion. With these two aims, we
will be able to discriminate between competing hypotheses about the mechanism of Serinc restriction of
HIV infection, gain a better understanding of how HIV transmits in the placenta, and potentially enable
the development of new anti-virals.

## Key facts

- **NIH application ID:** 10119157
- **Project number:** 5F30HD101348-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Amanda Elizabeth Ward
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2020-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119157

## Citation

> US National Institutes of Health, RePORTER application 10119157, Mechanistic investigations of HIV restriction by Serincs (5F30HD101348-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10119157. Licensed CC0.

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