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Review
. 2023 Oct 16;20(1):73.
doi: 10.1186/s12987-023-00476-7.

Occludin: a gatekeeper of brain Infection by HIV-1

Silvia Torices  1 , Leah Daire  1 , Sierra Simon  1 , Oandy Naranjo  1 , Luisa Mendoza  1 , Timea Teglas  1 , Nikolai Fattakhov  1 , Daniel Adesse  1   2 , Michal Toborek  3
Affiliations
Review

Occludin: a gatekeeper of brain Infection by HIV-1

Silvia Torices et al. Fluids Barriers CNS. .

Abstract

Compromised structure and function of the blood-brain barrier (BBB) is one of the pathological hallmarks of brain infection by HIV-1. BBB damage during HIV-1 infection has been associated with modified expression of tight junction (TJ) proteins, including occludin. Recent evidence indicated occludin as a redox-sensitive, multifunctional protein that can act as both an NADH oxidase and influence cellular metabolism through AMPK kinase. One of the newly identified functions of occludin is its involvement in regulating HIV-1 infection. Studies suggest that occludin expression levels and the rate of HIV-1 infection share a reverse, bidirectional relationship; however, the mechanisms of this relationship are unclear. In this review, we describe the pathways involved in the regulation of HIV-1 infection by occludin. We propose that occludin may serve as a potential therapeutic target to control HIV-1 infection and to improve the lives of people living with HIV-1.

Keywords: Blood brain barrier; HIV; Occludin; Virus.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Blood Brain Barrier (BBB) in HIV-1 infected brain and occludin structure. (A) Schematic representation of CNS invasion by HIV-1. After infecting leukocytes in the blood (monocytes and T-cells), HIV-1 can cross the BBB via the Trojan horse mechanism and infect various CNS cells, such as astrocytes, pericytes, and microglia cells. Moreover, brain infection by HIV-1 is associated with a disruption of the BBB integrity by altering tight junction (TJ) protein expression and function. (B) Schematic representation of the TJs formed by transmembrane proteins (e.g., occludin, claudins, and junctional adhesion molecules [JAM]). (C) Schematic representation of occludin structure, showing the domains and phosphorylation residues
Fig. 2
Fig. 2
HIV-1 infection in human brain pericytes under low (left panel) and high (right panel) occludin levels. A decrease in occludin leads to NAD + depletion, decreasing SIRT1 phosphorylation and increasing NF-κB acetylation, which leads to an increase in HIV-1 replication. In contrast, elevated occludin levels act as an HIV-1 inhibitor by increasing NAD+, following with an increase in phosphorylation of SIRT1 and a decrease in NF-κB acetylation. Moreover, elevated occludin levels increase the expression of interferon-stimulates genes (ISGs) such as the antiviral OAS gene family which degrades viral RNA and provides antiviral protection
Fig. 3
Fig. 3
Proposed model of signaling pathways influencing HIV-1 infection by modulation of occludin expression and function. Occludin functions are regulated by phosphorylation processes. Src, PKC, Rho-ROCK, VEGF, and PI3K-AKT-PTEN kinases can both alter occludin phosphorylation status and influence HIV-1 infection in several cell types. We propose that occludin phosphorylation may serve as one of the targets to modulate HIV-1 infection
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