# The Spinal Cord as a CNS Latent Reservoir for Replication Competent SIV

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $779,116

## Abstract

PROJECT SUMMARY
HIV infects macrophages in the spinal cord and brain, often leading to clinical symptoms even with
antiretroviral treatment (ART). In spinal cord and brain, macrophages (MΦs) may serve as long-term cellular
reservoirs of latent HIV. Replication competent HIV can emerge from these latent reservoirs if ART is stopped.
SIV replicates in both spinal cord and brain at equivalent levels during acute infection; however, the specific
cellular targets of SIV in the CNS have not been classified throughout infection, including during latency and
rebound after interrupting ART. In contrast with acute infection, viral dynamics are significantly different in
these distinct CNS compartments after stopping ART and tracking SIV rebound. SIV RNA is readily detectable
in spinal cord in the first weeks after stopping ART; in contrast, most SIV-infected animals do not have
detectable SIV RNA in the brain. The disparity in rebound replication between spinal cord and brain may result
from unique cellular immune responses by MΦ and astrocytes in these distinct CNS compartments. Most SIV-
infected macaques receiving ART have no detectable SIV RNA in spinal cord or brain, CSF, or plasma.
Proviral DNA and immune responses persist nonetheless in both spinal cord and brain. Intriguingly, the nature
of the sustained immune response differs: in the spinal cord, elevated expression of both GFAP and CCL2
point to sustained astrocyte activation; in the brain, elevated CD68 and TNFα levels indicate persistent brain
MΦ activation. The central premise of this proposal is that spinal cord MΦs serve as a distinct SIV reservoir in
the CNS that reactivates rapidly after stopping ART. Cellular neuroimmune responses in the spinal cord differ
from the brain during latency and reactivation after stopping ART. In particular, coordinate regulation of spinal
cord MΦ and astrocyte immune responses intrinsically differ from brain responses. Specific Aim 1 is to
determine whether spinal cord MΦs constitute a unique SIV reservoir in the CNS by identifying SIV-infected
CNS cell populations during 1) acute SIV infection, 2) prolonged latency with ART, and 3) viral rebound after
stopping ART. Specific Aim 2 will identify the neuroinflammatory responses in the spinal cord and brain during
1) acute SIV infection, 2) prolonged latency on ART, and 3) viral rebound after stopping ART. Gene expression
profiling will be performed using nCounter immunoregulatory assays; single cell RNA-seq gene expression
profiling performed on single cells isolated from spinal cord and brain including MΦs and astrocytes will
complement targeted gene profiling. Specific Aim 3 is to determine whether depleting spinal cord and brain
MΦs during latency and continuing after stopping ART by treatment with the CSF1R inhibitor PLX3397 alters
CNS SIV replication during SIV rebound from latency. MΦ depletion will complement SA1 studies on CNS
MΦs as latent reservoirs and SA2 studies on spinal cord gene expression prof...

## Key facts

- **NIH application ID:** 10830903
- **Project number:** 5R01NS113703-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** JOSEPH L MANKOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $779,116
- **Award type:** 5
- **Project period:** 2019-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830903

## Citation

> US National Institutes of Health, RePORTER application 10830903, The Spinal Cord as a CNS Latent Reservoir for Replication Competent SIV (5R01NS113703-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830903. Licensed CC0.

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