HIV-1 gp41 ectodomain enhances Cryptococcus neoformans binding to human brain microvascular endothelial cells via gp41 core-induced membrane activities

Cryptococcus neoformans causes life-threatening meningoencephalitis, particularly prevalent in AIDS patients. The interrelationship between C. neoformans and HIV-1 is intriguing, as both pathogens elicit severe neuropathological complications. We have previously demonstrated that the HIV-1 gp41 ectodomain fragments gp41-I33 (amino acids 579–611) and gp41-I90 (amino acids 550–639) can enhance C. neoformans binding to HBMECs (human brain microvascular endothelial cells). Both peptides contain the loop region of gp41. In the present study, we used immunofluorescence microscopy and transmission and scanning electron microscopy to explore the underlying mechanisms. Our findings indicated that both C. neoformans and gp41-I90 up-regulated ICAM-1 (intercellular adhesion molecule 1) on the HBMECs and elicited membrane ruffling on the surface of HBMECs. The HIV-1 gp41 ectodomain could also induce CD44 and β-actin redistribution to the membrane lipid rafts, but it could not enhance PKCα (protein kinase Cα) phosphorylation like C. neoformans. Instead, gp41-I90 was able to induce syncytium formation on HBMECs. The results of the present study suggest HIV-1 gp41-enhanced C. neoformans binding to HBMECs via gp41 core domain-induced membrane activities, revealing a potential mechanism of invasion for this pathogenic fungus into the brain tissues of HIV-1-infected patients.

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CD44-mediated monocyte transmigration across Cryptococcus neoformans-infected brain microvascular endothelial cells is enhanced by HIV-1 gp41-I90 ectodomain

Journal of Biomedical Science ◽

10.1186/s12929-016-0247-2 ◽

2016 ◽

Vol 23 (1) ◽

Cited By ~ 10

Author(s):

Xiaolong He ◽

Xiaolu Shi ◽

Santhosh Puthiyakunnon ◽

Like Zhang ◽

Qing Zeng ◽

...

Keyword(s):

Endothelial Cells ◽

Cryptococcus Neoformans ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Microvascular Endothelial ◽

Hiv 1

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Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases

Journal of Virology ◽

10.1128/jvi.79.7.4257-4269.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4257-4269 ◽

Cited By ~ 45

Author(s):

Edward A. Acheampong ◽

Zahida Parveen ◽

Lois W. Muthoga ◽

Mehrnush Kalayeh ◽

Muhammad Mukhtar ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Endothelial Cells ◽

Human Brain ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Immunodeficiency Virus ◽

Microvascular Endothelial ◽

Hiv 1

ABSTRACT The lentiviral protein Nef plays a major role in the pathogenesis of human immunodeficiency virus type I (HIV-1) infection. Although the exact mechanisms of its actions are not fully understood, Nef has been shown to be essential for the maintenance of high-titer viral replication and disease pathogenesis in in vivo models of simian immunodeficiency virus infection of monkeys. Nef has also been suggested to play a pivotal role in the depletion of T cells by promoting apoptosis in bystander cells. In this context, we investigated the ability of extracellular and endogenously expressed HIV-1 Nef to induce apoptosis in primary human brain microvascular endothelial cells (MVECs). Human brain MVECs were exposed to baculovirus-expressed HIV-1 Nef protein, an HIV-1-based vector expressing Nef, spleen necrosis virus (SNV)-Nef virus (i.e., SNV vector expressing HIV-1 Nef as a transgene), and the HIV-1 strain ADA and its Nef deletion mutant, ADAΔNef. We observed that ADA Nef, the HIV-1 vector expressing Nef, and SNV-Nef were able to induce apoptosis in a dose-dependent manner. The mutant virus with a deletion in Nef was able to induce apoptosis in MVECs to modest levels, but the effects were not as pronounced as with the wild-type HIV-1 strain, ADA, the HIV-1-based vector expressing Nef, or SNV-Nef viruses. We also demonstrated that relatively high concentrations of exogenous HIV-1 Nef protein were able to induce apoptosis in MVECs. Gene microarray analyses showed increases in the expression of several specific proapoptotic genes. Western blot analyses revealed that the various caspases involved with Nef-induced apoptosis are processed into cleavage products, which occur only during programmed cell death. The results of this study demonstrate that Nef likely contributes to the neuroinvasion and neuropathogenesis of HIV-1, through its effects on select cellular processes, including various apoptotic cascades.

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