CD4-Independent Human Immunodeficiency Virus Infection Involves Participation of Endocytosis and Cathepsin B

Yoshii, Hiroaki; Kamiyama, Haruka; Kensuke, Goto; Oishi, Kazunori; Katunuma, Nobuhiko; Tanaka, Yuetsu; Hayashi, Hideki; Matsuyama, Tomohiro; Sato, Hironori; Yamamoto, Naoki; Kubo, Yasuo

doi:10.1371/journal.pone.0019352

Cited by 25 publications

(28 citation statements)

References 61 publications

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“…These results are consistent with our in-vitro findings that HIV infection upregulates secretion of active cathepsin B by cultured MDM [12]. Two recent studies have suggested roles for cathepsin B in HIV infection [31] and/or release from infected cells [32], but in our study, we found no correlation of cathepsin B levels with plasma HIV-1 RNA copy number or viral load. Previous studies showed that cystatin B expression is induced in cultured MDM after HIV infection [17], and this protein has been associated with HIV replication in MDM [33].…”

Section: Discussionsupporting

confidence: 93%

Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

Cantres-Rosario¹,

Plaud-Valentín

Gerena³

et al. 2013

Aids

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Objective HIV-1-associated neurocognitive disorders (HAND) is triggered by immune activation of brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and cystatins are lysosomal proteins secreted by macrophages and microglia, and may play important roles in neuroregulatory responses. Our laboratory has shown increased secretion and neurotoxicity of cathepsin B from in-vitro HIV-infected monocyte-derived macrophages, and increased expression in postmortem brain tissue with HIV encephalitis and HAND. We hypothesized that cystatin B and cathepsin B could represent potential biomarkers for HAND. Methods Monocytes, plasma, and cerebrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for cystatins B and C and cathepsin B expression and activity. Results Increased cathepsin B and cystatins B and C were found in plasma of HIV-seropositive women. Higher intracellular expression of cathepsin B and cystatin B were found in monocytes from women with HIV-associated dementia (P <0.05). Significant increase in cystatin B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. Conclusion These results demonstrate that dysregulation of cystatin B–cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of cystatin B and cathepsin B in monocytes could be potential candidate biomarkers for HIV dementia, whereas increased cathepsin B and cystatins B and C in plasma are potential candidate markers of chronic HIV-1 activation.

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Section: Discussionsupporting

confidence: 93%

Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

Cantres-Rosario¹,

Plaud-Valentín

Gerena³

et al. 2013

Aids

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“…However, high levels of cystatin C prevented the secretion of cathepsin B but did not diminish its activity. These findings are confirmed by studies that reported the sequestration of cystatin C in the cytoplasm, increased levels of intracellular enzyme, and a concomitant decrease in extracellular levels during late HIV infection (Yoshii et al 2011). This could be a mechanism of cellular protection against increments in cytoplasmic cathepsin B released from lysosomes after infection.…”

Section: Discussionsupporting

confidence: 74%

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

et al. 2015

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BACKGROUND HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we request if microglia respond to HIV infection similarly by modifying the expression, secretion, neurotoxic potential of cathepsin B and the in vivo relevance of these findings. METHODS HIV-ADA infected human primary microglia and CHME-5 were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIVE patients. RESULTS HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at days 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. CONCLUSIONS Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.

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“…In addition, there is evidence that different Env glycoproteins can direct the virus entry through distinct routes. Entry of some CD4-independent HIV strains appears to require low pH and endocytic machinery [10,54,55]. Also, the block for the HIV-2 MCR infection in non-permissive cells can be rescued by pseudotyping this virus with HIV-1 Env, by inhibiting clathrin-/dynamin-dependent uptake or by disrupting actin filaments [56,57].…”

Section: A Model For Hiv Entry and Fusionmentioning

confidence: 99%

HIV entry: a game of hide-and-fuse?

Melikyan

2014

Current Opinion in Virology

101

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Human Immunodeficiency Virus (HIV) initiates infection by fusing its envelope membrane with the cell membrane through a process which is triggered through interactions with the cellular receptor and coreceptor. While the mechanism of HIV fusion has been extensively studied, the point of its entry into cells remains controversial. HIV has long been thought to fuse directly with the cell plasma membrane. However, several lines of evidence suggest that endocytic entry of HIV can lead to infection and, moreover, that endocytosis could be the predominant HIV entry pathway into different cell types. This review discusses recent findings pertinent to HIV entry routes and novel approaches to pinpoint the sites of virus entry.

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CD4-Independent Human Immunodeficiency Virus Infection Involves Participation of Endocytosis and Cathepsin B

Cited by 25 publications

References 61 publications

Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

HIV entry: a game of hide-and-fuse?

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