# Investigating the Env-dependent antiviral activity and Nef-mediated antagonism of SERINC5 in HIV-1 infection

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $18,218

## Abstract

The HIV-1 proteome consists of required structural and essential regulatory proteins as well as
accessory proteins that increase viral fitness. These accessory proteins, Vif, Vpr, Vpu, and Nef, are involved in
countering host immune responses and antagonizing so-called restriction factors, thereby increasing viral
infectivity, the ability of a virion to infect and replicate in target cells.
 Nef, or negative factor, has a variety of activities, most of which involve modulation of signal
transduction or membrane protein sorting. Nef increases the infectivity of viral particles (virions), with a
mechanism that depends on cellular endosomal proteins as well as on sequences within the viral Envelope
glycoprotein (Env).
 Two members of the serine incorporator (SERINC) protein family were identified recently as host
proteins that inhibit viral infectivity and are antagonized by Nef. SERINC5 (SERC5) is the most active; it
incorporates into virions and inhibits virion infectivity, potentially by altering the kinetics of virion-target cell
fusion, the function of the Env protein. Despite the prevailing model that SERC5 incorporates into virions to
inhibit Env function, it does not seem to co-immunoprecipitate with Env, suggesting the requirement of
cofactors or other indirect interactions. Moreover, different Env proteins are differentially sensitive to SERC5,
but the structural and molecular determinants of SERC5-sensitivity are unclear. To inhibit SERC5 antiviral
activity, Nef coordinates with endosomal machinery to relocalize SERC5 from the plasma membrane to late
endosomes. However, this model of SERC5-inhibition is derived solely from experiments in which exogenous
SERC5 is expressed. Whether endogenous SERC5 is similarly modulated is unknown.
 Here studies are proposed to determine the mechanisms behind SERC5-mediated restriction of virion
infectivity and Nef-mediated counteraction of this effect. Preliminary analysis of clade B Envs leads to the
hypothesis that a region within the gp41 membrane proximal external region (MPER) is responsible for
SERC5-sensitivity. This region and other putative determinants will be probed by site-directed mutagenesis. To
determine whether a direct interaction of SERC5 with Env can explain antiviral activity, or instead whether
SERC5-cofactors are responsible, a proximity-based labeling approach using APEX2, coupled with mass
spectrometry-based proteomics, will be used to probe the interactions of SERC5 and Env. Lastly, the
hypothesis that Nef downregulates endogenous SERC5 from the cell surface and traps it in late endosomes
via clathrin-mediated endocytosis will be tested using cell fractionation by differential centrifugation and
targeted proteomics to track the native, endogenous, unlabeled protein. When these experiments are
completed, the field will have a better explanation of the effect of SERC5 on HIV-1 virion infectivity. This
understanding might provide new approaches to restricting transmission, a pillar ...

## Key facts

- **NIH application ID:** 10237249
- **Project number:** 5F31AI141111-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Aaron Louis Oom
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $18,218
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-10-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237249

## Citation

> US National Institutes of Health, RePORTER application 10237249, Investigating the Env-dependent antiviral activity and Nef-mediated antagonism of SERINC5 in HIV-1 infection (5F31AI141111-04). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10237249. Licensed CC0.

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