# Targeted inactivation of HIV in CNS reservoirs

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $735,090

## Abstract

ABSTRACT
 HIV infection has been reported in various cells in the CNS, especially microglia. The CNS is also likely
to contribute to the reservoir of HIV infection that persists despite ART, although the contribution of the CNS to
viral rebound when ART is discontinued has not been clearly established. While a precise understanding of all
the body's reservoir(s) is lacking, contributing factors are expected to include gross anatomic features that
impact drug penetration and immune surveillance, as well as the transcriptional environment of specific cell
types that can lead to post-integration latency. In the case of the brain microglial population, they are not only
highly susceptible to HIV infection, but they reside in a compartment that is immune privileged and poorly
accessible to many drugs. There is also increasing evidence that between 30 and 50% of well-suppressed HIV
patients have neurocognitive dysfunction (HAND), suggesting that even a low level of persistent HIV in the
brain can cause neurological damage. Thus, it is crucial to develop strategies that can remove, disable or
suppress HIV in the CNS, ideally using methods that do not require viral reactivation because of the risk of
exacerbating neuronal damage. One such approach being considered is based on disabling or suppressing
HIV replication using sequence-specific genetic tools. By targeting HIV at the genetic level, a powerful suite of
emerging technologies could be leveraged for this goal, including RNAi to prevent HIV translation, and
engineered nucleases to disrupt, suppress, or epigenetically silence integrated HIV genomes. However, two
major problems exist for the development and evaluation of such tools for HIV-CNS reservoir applications.
First, efficient methods to specifically deliver the reagents to the CNS need to be developed. Targeting HIV
reservoir cells is challenging because of the relative rarity of such cells and because a truly latent cell will not
express any phenotypic indicators of its viral passenger. The second major issue is that successful delivery
requires properties beyond simple target molecule recognition, including in vivo stability, de-targeting away
from vascular sinks, and the ability to enter the CNS. Unfortunately, such complex parameters can only be
evaluated in an animal model. To contribute to the broad effort towards an HIV cure, and its many significant
technical challenges, we have developed a semi-quantitative model of latent HIV infection in the CNS, based
on human microglial cell engraftment in immune-deficient mice reconstituted with human hematopoietic stem
cells. The animals contain up to 10% human CD11b+ microglia and perivascular macrophages and can be
infected with HIV-1. After suppression of viral replication by ART, infected cells can be recovered from their
brains. The current iteration of the model, and anticipated refinements to increase microglial cell populations in
these animals, will be used to systematically evaluate t...

## Key facts

- **NIH application ID:** 9851965
- **Project number:** 5R01MH113457-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Paula M Cannon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,090
- **Award type:** 5
- **Project period:** 2017-04-20 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851965

## Citation

> US National Institutes of Health, RePORTER application 9851965, Targeted inactivation of HIV in CNS reservoirs (5R01MH113457-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851965. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*