# Combined Molecular Excision Therapy (CMET) for Eliminating HIV-1

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $680,886

## Abstract

Abstract
The elimination of the human immunodeficiency virus (HIV) from its central nervous system (CNS) and
peripheral reservoirs is a requirement for a disease-cure. To our knowledge, we are the first to have achieved
this goal in tests performed in a limited number of infected humanized mice. To validate such early successes
we propose to build a four-step ladder with a final crest of latent virus eradication. First, a newly developed
humanized mouse brain-lymphoid model of neuroAIDS will identify productively infected perivascular and
meningeal macrophages and restricted infection in parenchymal cells. This rodent model most closely reflects
human brain disease as demonstrated by robust molecular, virologic and neuroimmunologic tests. Second,
long acting slow effective release antiretroviral therapy (LASER ART) also now fully developed in our
laboratories can now facilitate a pinpoint localization of the latently infected viral brain reservoir. Third, viral
excision strategies will be employed to eliminate residual virus and preclude HIV reactivation. The gene editing
CRISPR/Cas9 system developed by Temple University Medical Center investigators including CCR5 and viral
excision strategies will reduce then eliminate any ongoing infection and integrated proviral DNA from infected
cells. The CRISPR/Cas9 constructs will deliver its cargo to brain and peripheral tissue sites using specific
serotypes of adeno-associated virus. This will enable permanent HIV eradication in humanized mice without
viral reactivation and as such preclude any ongoing brain infection and subsequent neural damage. Fourth, in
order to prove the therapeutic strategy effective both for brain and peripheral lymphoid tissue virus (including
the gut-associated lymphoid tissue, lymph node, spleen and genitourinary system) we will cease ART
administrations and following time periods measured in months to provide cross validating evidence for viral
eradication by measure rebound. Given the risks associated with HIV reactivation in the CNS this approach
must show effectiveness for its abilities to target latent virus. Taken together, the proposal seeks support to
employ combination LASER ART and potent molecular viral and immune-based regimens for elimination of
viral depots. The overall premise is to develop the “state of the art” tools required to permanently eliminate
virus detected in the CNS and peripheral infectious reservoirs.

## Key facts

- **NIH application ID:** 9989182
- **Project number:** 5R01MH115860-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Howard E Gendelman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $680,886
- **Award type:** 5
- **Project period:** 2017-09-20 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989182

## Citation

> US National Institutes of Health, RePORTER application 9989182, Combined Molecular Excision Therapy (CMET) for Eliminating HIV-1 (5R01MH115860-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989182. Licensed CC0.

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