# Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $734,726

## Abstract

HIV entry into the CNS occurs early after peripheral infection and is mediated by the transmigration of infected
monocytes across the BBB, establishing CNS viral reservoirs, neuronal damage, and low level inflammation,
despite antiretroviral therapy (ART), that mediate HIV-associated neurocognitive disorders, HAND, in >50% of
infected people even in those with undetectable virus. The mechanisms of HIV infected monocyte
transmigration across the BBB have only been minimally characterized. A mature CD14+CD16+ monocyte
subset is key to HIV CNS pathogenesis. We showed that these cells selectively transmigrate across our model
of the human BBB in response to the chemokine CCL2, and that when HIV infected, they transmigrate in even
greater numbers. This is due, in part, to their increased junctional proteins JAM-A and ALCAM, and increased
CCR2, the receptor for CCL2. CD14+CD16+ monocytes in HIV-infected individuals are heterogeneous,
consisting of cells that are infected with HIV (HIV+), and cells exposed to viral and host factors, but not infected
with the virus (HIVexp). It is not known whether the transmigration of HIV+ and HIVexp CD14+CD16+ monocytes
across the BBB differs, and how this affects CNS neuropathogenesis. HIV+ monocytes that cross the BBB may
differentiate into long-lived CNS macrophages and establish and maintain CNS viral reservoirs contributing to
CNS damage. With ART, productively infected CD14+CD16+ monocytes in the peripheral blood are
significantly reduced, with a small number of these cells still having detectable viral DNA. We propose that the
neuronal damage and chronic inflammation that mediate cognitive impairment, even in the presence of ART, is
dependent on continued reseeding of the brain with HIV+CD14+CD16+ monocytes, maintaining CNS viral
reservoirs and continuing the influx of these infected as well as uninfected monocytes into the brain.
Mechanisms that ensure that these HIV+CD14+CD16+ monocytes replenish CNS viral reservoirs over extended
periods are not known. We hypothesize that CCR2, and junctional proteins are higher on HIV+ monocytes
compared to HIVexp monocytes, resulting in their preferential transmigration across the BBB, and that this is
associated with the establishment and maintenance of CNS viral reservoirs, and with neuronal and structural
damage, low level inflammation, and cognitive impairment. We will characterize HIV+ and HIVexp monocytes
using primary human mature CD14+CD16+ monocytes infected in vitro. We will also characterize the
phenotype and transmigration of HIV+ and HIVexp mature monocytes from a longitudinal cohort of HIV-infected
people stably suppressed on ART, and determine whether these circulating monocyte characteristics correlate
with cognitive impairment and neurobiologic abnormalities using neuroimaging. We will determine whether
CCR2, JAM-A, or ALCAM are biomarkers of HAND. We will use blocking antibodies and cenicriviroc in
transmigration assays to assess JAMA, ALCAM, and CCR2 as ...

## Key facts

- **NIH application ID:** 9915978
- **Project number:** 5R01MH112391-05
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Joan Weinberger Berman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $734,726
- **Award type:** 5
- **Project period:** 2017-07-19 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915978

## Citation

> US National Institutes of Health, RePORTER application 9915978, Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era (5R01MH112391-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9915978. Licensed CC0.

---

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