# Mechanisms underlying lncRNA SAF-mediated survival and persistence of HIV-1 infected macrophages

> **NIH NIH R21** · CORNELL UNIVERSITY · 2021 · $235,500

## Abstract

Project Summary / Abstract
 Combination anti-retroviral therapy is highly effective in blocking HIV-1 replication and thereby new
infections but it cannot eliminate reservoir cells infected prior to the treatment initiation. Most studies of HIV-1
persistence have focused on latently infected CD4+ T cells. However, tissue-resident macrophages which are
self-renewable, long-lived myeloid cells, have recently been shown to sustain prolonged viremia in absence of
T lymphocytes. The unique ability of macrophages to support HIV-1 replication without succumbing to virus-
induced cell death makes them ideal for viral persistence. Understanding the role of viral and host factors that
enable macrophages to evade cell death is needed to develop effective strategies for eliminating these
persistently infected myeloid cells.
 By screening a panel of 90 long non-coding RNAs (lncRNA), we have recently discovered the novel role
of the lncRNA SAF (FAS-AS1) in maintenance of cell survival of HIV-1 infected macrophages. This lncRNA is
significantly up-regulated in HIV-1 infected human monocyte-derived macrophages (MDM) in vitro and lung
alveolar macrophages (AM) in vivo. More importantly, siRNA-mediated inhibition of SAF leads to activation of
apoptotic caspases in HIV-1 infected macrophages selectively, while leaving the virus-exposed yet uninfected
bystander cells unaffected. This highly specific modulation of the lncRNA SAF results in a marked reduction in
viral burden in the macrophage culture, emphasizing the therapeutic potential of targeting this lncRNA. Our
central hypothesis is that active HIV-1 infection induces SAF up-regulation in macrophages to regulate cell
survival/death pathway(s) that promote viral persistence. We propose an in-depth analysis of both the upstream
regulators of SAF transcription and the downstream effectors for its function.
 Our specific aims are to: (1) define the viral and cellular regulators for induction of lncRNA SAF in HIV-1
infected macrophages; and (2) determine the molecular mechanisms of lncRNA SAF mediated protection of
HIV-1 infected macrophages from cell death by identifying the DNA/RNA and/or protein targets of this lncRNA.
We will use a panel of specific replication-stage-defective viruses in combination with state-of-the-art genetic
and proteomic tools (DNA/RNA-Seq, RNA antisense purification and LC-MS) to achieve our goals. The results
from this study will improve our basic scientific knowledge of the biology of a lncRNA in HIV-1 pathogenesis and
persistence in macrophages. It will also provide additional modalities for targeting SAF by identifying the
regulators and effectors of this lncRNA. Understanding the mechanisms underpinning SAF-mediated cell survival
and viral persistence in HIV-1 infected macrophages will aid greatly in optimally exploiting the novel therapeutic
potential of this lncRNA.

## Key facts

- **NIH application ID:** 10159666
- **Project number:** 1R21AI157759-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Saikat Boliar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2021-03-17 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159666

## Citation

> US National Institutes of Health, RePORTER application 10159666, Mechanisms underlying lncRNA SAF-mediated survival and persistence of HIV-1 infected macrophages (1R21AI157759-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10159666. Licensed CC0.

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