# Are HIV-1-Infected Alveolar Macrophages Productive Sites of Viral Persistence?

> **NIH NIH R33** · CORNELL UNIVERSITY · 2021 · $413,352

## Abstract

Project Summary / Abstract
 Despite several reports of HIV-1-infected alveolar macrophages (AM) in the lungs of HIV-1-infected
individuals, the roles played by these cells in the maintenance or persistence of infection remain unresolved.
Recent studies in Malawi, conducted on AM from HIV-1-infected individuals that are effectively virally-
suppressed by long-term ART, reproducibly detected the presence of HIV-1 mRNA by fluorescent in situ
hybridization (FISH). In these studies, we also detected HIV-1 transcripts through single cell sequencing
protocols, and have isolated infectious HIV-1 virus from cells recovered by bronchoalveolar lavage from ART-
naïve, HIV-1-infected volunteers.
The hypothesis we propose to test is that the presence of HIV-1 transcripts in the alveolar macrophages of HIV-
infected individuals is indicative of a productive viral infection that has significance for persistence of the virus
during ART.
R21 Phase: Aim 1. Are HIV-1-infected AM productively infected?
We propose co-culture approaches to detect and capture infectious HIV-1 from the AM and peripheral blood of
HIV-1-infected volunteers in Malawi. Using permissive, HIV-1-susceptible reporter cells we have already shown
that we can acquire infectious virus from ART-naïve individuals in a pilot study on 12 volunteers. We propose
expanding this analysis to a larger cohort, including ART-treated, virally-suppressed individuals.
R33 Phase: Aim 2. Transcriptional Profiling of Viral and Host Transcripts in HIV-1-Infected Cells.
Using methods already established in Malawi, we will generate transcriptional profiles of HIV-infected and
uninfected AMs by single-cell Seq-Well and Flow-FISH RNASeq methods to obtain datasets reflecting both
single-cell resolution and depth of coverage. We will use these datasets to probe the impact of HIV-1 in cell
longevity and to study the cellular tropism of the envs from AM-derived HIV-1 virus.
R33 Phase: Aim 3. Perturbation of HIV-1-infected AM Function with Synthetic mRNA and SiRNA.
We will use gain-of-function (synthetic mRNA) and loss-of-function (siRNA) approaches to manipulate the
phenotype and behavior of HIV-1-infected HMDMs and AMs. The goal is to identify pathways that will drive
programmed cell death specifically in those AMs that are HIV-1-infected as a route for selective eradication of
this potential viral reservoir.
The proposal is based on the contention that AM in virally-suppressed individuals will prove to be productively-
infected. The verification of this contention is the major milestone of the R21 period of this phased award.

## Key facts

- **NIH application ID:** 10240741
- **Project number:** 5R33AI136097-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** DAVID G RUSSELL
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,352
- **Award type:** 5
- **Project period:** 2018-01-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240741

## Citation

> US National Institutes of Health, RePORTER application 10240741, Are HIV-1-Infected Alveolar Macrophages Productive Sites of Viral Persistence? (5R33AI136097-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240741. Licensed CC0.

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