# Tethering lentiviral restriction to Fc-mediated antibody responses

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $763,634

## Abstract

PROJECT SUMMARY
Tetherin, also known as BST-2 or CD317, is an interferon-inducible transmembrane protein that inhibits the
detachment of enveloped viruses from infected cells. Under conditions of interferon-induction, tetherin is
upregulated on virus-infected cells and captures nascent virions as they attempt to bud from the cell surface.
Whereas most simian immunodeficiency viruses (SIVs) use Nef to oppose the tetherin proteins of their
nonhuman primate hosts, HIV-1 Vpu and HIV-2 Env have acquired the ability to counteract human tetherin
because of the absence of a five amino acid sequence in human tetherin that confers susceptibility to Nef. We
previously demonstrated that tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent
cellular cytotoxicity (ADCC). We now show that the anti-tetherin activity of Vpu also protects HIV-infected cells
from antibody-dependent cellular phagocytosis (ADCP). These findings imply that by trapping virions on the
cell surface, tetherin increases the sensitivity of HIV-infected cells to Fc-mediated antibody responses, and that
the antiviral activity of tetherin may be much greater in vivo than previously appreciated. The current proposal
builds on these studies to address the overarching hypothesis that tetherin serves as link between innate and
adaptive immunity to enhance the susceptibility of virus-infected cells to antibodies.
In Aim 1, we will determine the immunological mechanisms by which tetherin enhances antibody-mediated
phagocytosis of HIV-infected cells. These studies will focus on the factors that influence the extent to which
tetherin can promote ADCP, which will provide a better understanding of how to use these interactions to
improve antibody-based treatments for HIV-1 infection. In Aim 2, we will take advantage of the power of SIV
infection of the rhesus macaque as an animal model to assess the contribution of viral countermeasures to
tetherin and SERINC5 to lentiviral replication and pathogenesis. These studies will reveal the impact of tetherin
and SERINC5 on lentiviral infection and the therapeutic benefit that may be derived from antiretroviral drugs
designed to increase the sensitivity of HIV-1 to these restriction factors. In Aim 3, we will test the hypothesis
that tetherin enhances antibody-mediated control of virus replication in SIV-infected macaques. These studies
are fundamental to our basic understanding of the synergy between tetherin and antibodies and the potential to
exploit these interactions for the treatment and prevention of HIV-1 infection.

## Key facts

- **NIH application ID:** 10873836
- **Project number:** 5R01AI155163-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** David T Evans
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $763,634
- **Award type:** 5
- **Project period:** 2020-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873836

## Citation

> US National Institutes of Health, RePORTER application 10873836, Tethering lentiviral restriction to Fc-mediated antibody responses (5R01AI155163-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873836. Licensed CC0.

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