Mechanisms of HIV Neuropathogenesis: Role of Cellular Communication Systems

Malik, Susanta; Eugenín, Eliseo A.

doi:10.2174/1570162x14666160324124558

Cited by 43 publications

(48 citation statements)

References 143 publications

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“…This new route of HIV transmission was later confirmed by observations of HIV dissemination in vivo within lymph nodes of humanized mice (24). "Hijacking" of TNTs and other cellular communication pathways by HIV enhances viral transmission to large populations of cells and is considered an important factor in HIV neuropathogenesis and in the establishment of viral reservoirs (25). Moreover, the HIV accessory protein Nef has been shown to stimulate the formation of tunneling nanotubes and virological synapses (26).…”

mentioning

confidence: 89%

Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Panasiuk

Rychłowski

Derewońko

et al. 2018

J Virol

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Various types of intercellular connections that are essential for communication between cells are often utilized by pathogens. Recently, a new type of cellular connection, consisting of long, thin, actin-rich membrane extensions named tunneling nanotubes (TNTs), has been shown to play an important role in cell-to-cell spread of HIV and influenza virus. In the present report, we show that TNTs are frequently formed by cells infected by an alphaherpesvirus, bovine herpesvirus 1 (BoHV-1). Viral proteins, such as envelope glycoprotein E (gE), capsid protein VP26, and tegument protein Us3, as well as cellular organelles (mitochondria) were detected by immunofluorescence and live-cell imaging of nanotubes formed by bovine primary fibroblasts and oropharynx cells (KOP cells). Time-lapse confocal studies of live cells infected with fluorescently labeled viruses showed that viral particles were transmitted via TNTs. This transfer also occurred in the presence of neutralizing antibodies, which prevented free entry of BoHV-1. We conclude that TNT formation contributes to successful cell-to-cell spread of BoHV-1 and demonstrate for the first time the participation of membrane nanotubes in intercellular transfer of a herpesvirus in live cells. Efficient transmission of viral particles between cells is an important factor in successful infection by herpesviruses. Herpesviruses can spread by the free-entry mode or direct cell-to-cell transfer via cell junctions and long extensions of neuronal cells. In this report, we show for the first time that an alphaherpesvirus can also spread between various types of cells using tunneling nanotubes, intercellular connections that are utilized by HIV and other viruses. Live-cell monitoring revealed that viral transmission occurs between the cells of the same type as well as between epithelial cells and fibroblasts. This newly discovered route of herpesviruses spread may contribute to efficient transmission despite the presence of host immune responses, especially after reactivation from latency that developed after primary infection. Long-range communication provided by TNTs may facilitate the spread of herpesviruses between many tissues and organs of an infected organism.

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mentioning

confidence: 89%

Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Panasiuk

Rychłowski

Derewońko

et al. 2018

J Virol

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“…The lateral localization of Cx43 protein and the separation between the different muscle fibers suggest that Cx43 hemichannels may be an additional source of cellular compromise and inflammation as described in other systems. 58,61,62 Opening of Cx43 hemichannels would increase Ca 2þ influx into cardiomyocytes and allow Na þ influx, and K þ efflux and loss of ATP and other metabolites into the extracellular space. In agreement with the suggestion of increased hemichannel opening, our data indicate that all HIV-infected individuals have increased circulation of intracellular molecules transported by the opening of hemichannels.…”

Section: Discussionmentioning

confidence: 99%

HIV-Associated Cardiovascular Disease

Prevedel

Morocho

Bennett

et al. 2017

The American Journal of Pathology

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Chronic HIV infection due to effective antiretroviral treatment has resulted in a broad range of clinical complications, including accelerated heart disease. Individuals with HIV infection have a 1.5 to 2 times higher incidence of cardiovascular diseases than their uninfected counterparts; however, the underlying mechanisms are poorly understood. To explore the link between HIV infection and cardiovascular diseases, we used postmortem human heart tissues obtained from HIV-infected and control uninfected individuals to examine connexin 43 (Cx43) expression and distribution and HIV-associated inflammation. Here, we demonstrate that Cx43 is dysregulated in the hearts of HIV-infected individuals. In all HIV heart samples analyzed, there were areas where Cx43 was overexpressed and found along the lateral membrane of the cardiomyocyte and in the intercalated disks. Areas of HIV tissue with anomalous Cx43 expression and localization also showed calcium overload, sarcofilamental atrophy, and accumulation of collagen. All these changes were independent of viral replication, CD4 counts, inflammation, and type of antiretroviral treatment. Overall, we propose that HIV infection increases Cx43 expression in heart, resulting in tissue damage that likely contributes to the high rates of cardiovascular disease in HIV-infected individuals.

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“…The development of HIV-Associated Neurocognitive Disorders (HANDs) is one of the major complications of AIDS and cognitive impairment is found in approximately 50-60% of HIV-infected patients [69,70]. It has been shown that HIV-associated deleterious effects in the brain, particularly the neuronal loss is mediated through an increase in connexin 43 expression [71]. Unlike other viruses, HIV is shown to increase the expression of connexin 43 on the astrocytes, which is mainly attributed to the presence of HIV-tat protein.…”

Section: Deleterious Effects Of Connexins In Hiv-induced Dementiamentioning

confidence: 99%

Astroglial connexins and cognition: memory formation or deterioration?

Yang

et al. 2020

Bioscience Reports

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Connexins are the membrane proteins that form high-conductance plasma membrane channels and are the important constituents of gap junctions and hemichannels. Among different types of connexins, connexin 43 is the most widely expressed and studied gap junction proteins in astrocytes. Due to the key involvement of astrocytes in memory impairment and abundant expression of connexins in astrocytes, astroglial connexins have been projected as key therapeutic targets for Alzheimer’s disease. On the other hand, the role of connexin gap junctions and hemichannels in memory formation and consolidation has also been reported. Moreover, deletion of these proteins and loss of gap junction communication result in loss of short-term spatial memory. Accordingly, both memory formation and memory deteriorating functions of astrocytes-located connexins have been documented. Physiologically expressed connexins may be involved in the memory formation, while pathologically increased expression of connexins with consequent excessive activation of astrocytes may induce neuronal injury and cognitive decline. The present review describes the memory formation as well as memory deteriorating functions of astroglial connexins in memory disorders of different etiology with possible mechanisms.

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Mechanisms of HIV Neuropathogenesis: Role of Cellular Communication Systems

Cited by 43 publications

References 143 publications

Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

HIV-Associated Cardiovascular Disease

Astroglial connexins and cognition: memory formation or deterioration?

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