# Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2022 · $915,398

## Abstract

Project Summary
 The long-lived myeloid cells such as perivascular macrophages and microglia in the central nervous system
(CNS) persistently harbor HIV. These infected cells could contribute to the source of residual viremia during
long-term antiretroviral therapy (ART) or to rebounding virus upon ART cessation. It is undoubtfully and urgently
needed to develop novel strategies to specifically target CNS myeloid cells for HIV eradication and a cure. Be-
cause the effects of the widely-studied “Shock and Kill” approach could exacerbate neuroinflammation, gene
therapy emerges as the optimal strategy, particularly the advanced CRISPR genome editing technology. Simian
immunodeficiency virus (SIV) infection of macaques is the best available model for testing novel strategies prior
to clinical studies. We have shown that SIV infection has a broad spread in the CNS even in animals on ART.
Because the virus enters the brain within a few days after infection and the establishment of the latent reservoir
occurs very early, the initiation of ART should be as early as possible. In addition, numerous studies suggest
that CCR5/CCR2 play a major role in HIV entry and neuroinflammation. Most importantly, we have used AAV
delivery of a CRISPR/Cas genome editor to eradicate HIV/SIV provirus in models of humanized mice and non-
human primates. However, the lack of AAV serotypes that are highly effective and reliable to transduce myeloid
cells in the CNS remains a key challenge. Therefore, we hypothesize that the multiple-targeting gene editing
system across the blood brain barrier (BBB) can remove SIV provirus in infected myeloid cells, protect cells
against new infection, and inhibit neuroinflammation. To test this hypothesis, we will optimize a novel AAV sero-
type with BBB penetration and myeloid-specific transduction (namely AAV-BM) to effectively deliver the smaller
cjCas9 with multiplex sgRNAs (BMCj4) specific for 4 target sites (SIV LTR, gag, and host CCR5, CCR2) into the
entire CNS for in vivo HIV/SIV eradication (Aim 1). We will evaluate the efficacy of BMCj4 early treatment in
preventing brain SIV infection or/and excising SIV proviral DNA from brain myeloid cells in acute SIV infection
with early ART (Aim 2a). We will also determine the therapeutic effect of BMCj4 with ART and then boost it with
an alternative AAV-BM for eradication of persistent brain SIV latent infection (Aim 2b). We expect that early or
long-term repeated BMCj4 AAV gene therapy will effectively eradicate acute and latently-infected HIV provirus
and extensively minimize the size of the brain viral reservoir to achieve a sterilizing or functional cure of
HIV/AIDS, particularly NeuroAIDS.

## Key facts

- **NIH application ID:** 10476684
- **Project number:** 1R01MH130193-01
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Wenhui Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $915,398
- **Award type:** 1
- **Project period:** 2022-04-05 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476684

## Citation

> US National Institutes of Health, RePORTER application 10476684, Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication (1R01MH130193-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10476684. Licensed CC0.

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