# Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $525,407

## Abstract

Abstract:
As of 2014, an estimated 35 million persons worldwide were living with human immunodeficiency virus
(HIV). Early after primary infection, HIV enters the CNS and causes long lasting cognitive and motor
impairment in 30-60 % of infected individuals, even in the current antiretroviral era. As infected individuals
are living longer, the prevalence of neurological complications has been increasing. In the CNS, HIV
infects mostly microglia/macrophages, but also a small population of astrocytes. However, despite the key
roles of astrocytes in CNS functions, the role of these cells in NeuroAIDS has been relatively ignored. Our
studies during the last funding period provide strong evidence for the critical role of astrocytes in the
pathogenesis of NeuroAIDS. In particular, we have demonstrated that despite relatively low numbers of
infected astrocytes and low to undetectable HIV replication, the HIV infected astrocytes transmit apoptotic
and inflammatory signals, including calcium and inositol triphosphate (IP3), to neighboring uninfected cells,
promoting neuronal damage and demise. We have also shown that these pro-apoptotic molecules are
spread from the few HIV infected astrocytes via connexin-43 (Cx43) containing gap junctions (GJ) and
unopposed hemichannels (uHC), whose expression and opening is regulated by HIV. Indeed, blocking GJ
or uHC reduced amplification of bystander apoptosis, cellular dysfunction, synaptic compromise, and
mitochondrial dysfunction induced by HIV infected astrocytes. Interestingly, HIV infected astrocytes
themselves are protected from apoptosis by mechanisms that involve altered apoptosome formation and
mitochondrial function. Importantly, we have tested and validated most of the mechanisms operating in
HIV infected astrocytes in vivo in human and monkey brain tissue sections. Thus, based on the results
obtained during the extremely productive period funded by our first R01 (resulting in over 40 publications
in high quality peer reviewed journals) we have formulated our current hypothesis that “HIV infected
astrocytes survive HIV infection to become HIV reservoirs, and that these cells send toxic, pro-apoptotic
signals to surrounding cells via Cx43 containing channels, leading to the CNS dysfunction and
NeuroAIDS”. In this application we propose to characterize the novel pathways of HIV toxicity within the
brain and to identify the role of GJ and uHC in CNS dysfunction. The results obtained from this proposal
will lead to the identification of potential novel therapeutic targets to limit the devastating consequences of
NeuroAIDS.

## Key facts

- **NIH application ID:** 9914883
- **Project number:** 5R01MH096625-12
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Eliseo A Eugenin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,407
- **Award type:** 5
- **Project period:** 2012-05-07 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914883

## Citation

> US National Institutes of Health, RePORTER application 9914883, Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS (5R01MH096625-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914883. Licensed CC0.

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