# HIV restriction by APOBEC3A

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $466,130

## Abstract

Abstract
The human APOBEC3 locus is composed of seven different cytidine deaminase proteins (A3A to A3H) that
display antiviral activities against numerous viruses including HIV. Several of these host defense proteins, such
as A3G, are incorporated into virions and target HIV by mutating the single stranded viral DNA during reverse
transcription in the next cycle of infection. HIV, however, counteracts the antiviral activity of these APOBEC3
proteins by encoding the Vif accessory protein that leads to their proteasomal degradation in HIV producer
cells. The antiviral activity of A3A remains unclear in contrast to the better-characterized anti-HIV functions of
A3D, A3F, A3G and A3H. Of note, A3A is unique among the APOBEC3 cytidine deaminases because it
targets both DNA and RNA. Moreover its expression is potently induced by Type I Interferon in myeloid cells
such as macrophages and dendritic cells. Our preliminary findings using knockdown as well as overexpression
of A3A show that A3A inhibits HIV directly in the target cell. We hypothesize that A3A acts as a lentiviral
gatekeeper via a currently unknown mechanism. This hypothesis will be tested in three independent Specific
Aims. In Specific Aim 1, we will characterize the impact of A3A overexpression on HIV infection using a panel
of different HIV strains. Furthermore, we will perform CRISPR knockout experiments in myeloid cell lines and
primary human cells to test the antiviral role of endogenously expressed A3A. In Specific Aim 2, we will dissect
the mechanism of A3A restriction by defining at which step of the viral life cycle the block to infection occurs.
We will also measure A3A-induced mutagenesis by deep sequencing of HIV proviral DNA. In Specific Aim 3,
we will decipher the full spectrum of A3A transcript variation and protein expression in primary T lymphocytes
and myeloid cells stimulated with different interferons. Lastly, we will use CRISPR transactivation to induce
A3A expression in CD4+ T cells and determine the extent to which A3A renders these cells resistant to
infection by different HIV strains. Collectively, the proposed studies will elucidate the anti-HIV activity of A3A
and deliver mechanistic insights on how to exploit A3A to make susceptible human cells resistant to HIV.

## Key facts

- **NIH application ID:** 9963089
- **Project number:** 5R01AI120998-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Viviana A Simon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,130
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963089

## Citation

> US National Institutes of Health, RePORTER application 9963089, HIV restriction by APOBEC3A (5R01AI120998-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9963089. Licensed CC0.

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