# Nanopeptide Targeting of HIV-CNS Reservoirs without Reactivation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $649,766

## Abstract

At present, there are ~37 million people living with human immunodeficiency virus type-1 (HIV) infection
worldwide. Although AIDS and severe dementia have become uncommon with ART, minor cognitive motor
disorder (MCMD) remains an important manifestation of HIV infection affecting 10-30% of persons living with
HIV which may be increasing as the number of HIV-infected individuals in their 50s and 60s rises. Additionally,
though ART has led to significant virologic suppression and improvement in immune function, persistent viral
reservoirs remain that have been refractory to intensified antiviral therapy including macrophages and microglial
cells within the brain. Numerous strategies have been proposed to eradicate HIV persistence (both latent and
low level replicating virus). Most prominent has been the “shock and kill” approach that attempts to reactivate
virus with the hope of decreasing the reservoir size while preventing new cells from becoming infected. This
approach, however, could be detrimental to the CNS where viral reactivation including release of viral
components could exacerbate inflammation and neuronal dysfunction resulting in increased cognitive
impairment. Our previous research has indicated that autophagy is essential for the maintenance of cellular
homeostasis and persistence of HIV in viral reservoirs. However, despite being an essential survival mechanism,
excessive levels of autophagy are able to induce cell death. Recently, we have shown that an autophagy-
dependent non-apoptotic form of cell death, autosis, can be triggered by autophagy-inducing peptides through
the induction of Na+/K+-ATPase leading to HIV inhibition and the potential to preferentially kill HIV
latently/persistently infected cells including macrophages. In the research proposed, these peptides will be
loaded into lipid-coated polymeric nanoparticles that combine the positive attributes of both liposomes and
polymeric nanoparticles and optimized to allow passage across the blood-brain-barrier, This proposal will
leverage the unique experience of our research team in elucidating the molecular interactions of HIV and
autophagy, and in the development and use of nanoparticles to optimize drug delivery. The Specific Aims of
this proposal are: Aim 1: Preferential killing of HIV-infected macrophages, microglia and astrocytes without viral
reactivation. Aim 2: In vitro optimization of HIV eradication in macrophages, microglia and astrocytes resulting
in the least toxicity to neurons. Aim 3: Synthesis and optimization of peptide loaded sub-25 nm nanoparticles for
improved delivery to the CNS; and Aim 4: Elimination of HIV infected cells within the CNS in the murine model
of HIV encephalitis. This research will address the fundamental roadblocks to achieving HIV elimination within
the brain by: developing nanoparticles that facilitate peptide entry across the BBB; preferential killing of HIV-
infected cells within the CNS through induction of Na+K+-ATPase dependent a...

## Key facts

- **NIH application ID:** 9872219
- **Project number:** 5R01NS104015-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** STEPHEN A SPECTOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $649,766
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872219

## Citation

> US National Institutes of Health, RePORTER application 9872219, Nanopeptide Targeting of HIV-CNS Reservoirs without Reactivation (5R01NS104015-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872219. Licensed CC0.

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