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Role of endolysosomes in HIV-1 Tat-induced neurotoxicity.

Hui L, Chen X, Haughey NJ, Geiger JD - ASN Neuro (2012)

Bottom Line: Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder).As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy.In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.

ABSTRACT
Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder). Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription) protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND.

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HIV-1 Tat-induced neuronal cell death in a time-dependent mannerSignificant amounts of neuronal cell death were observed after 2-day incubation with HIV-1 Tat (100 nM) and reached a maximal level of 50% cell death by the fourth day. No significant neuronal cell death was observed in neurons treated with either mutant Tat or PBS (n = 5, *P<0.05 and ***P<0.001).
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Figure 1: HIV-1 Tat-induced neuronal cell death in a time-dependent mannerSignificant amounts of neuronal cell death were observed after 2-day incubation with HIV-1 Tat (100 nM) and reached a maximal level of 50% cell death by the fourth day. No significant neuronal cell death was observed in neurons treated with either mutant Tat or PBS (n = 5, *P<0.05 and ***P<0.001).

Mentions: In order to compare the effects of HIV-1 Tat on neuronal damage and the structure and function of endolysosomes, we needed to first determine the time course and extent to which HIV-1 Tat decreased neuronal viability. HIV-1 Tat1–72 induced significant amounts of neuronal cell death starting from 48 h of treatment (n = 5, P<0.05) with a maximum of 50% neuronal cell death (n = 5, P<0.001) after the treatment for 96 h (Figure 1). These data were consistent with previous studies that have shown similar neurotoxic effects of HIV-1 Tat (Kruman et al., 1998; Haughey et al., 1999; Bonavia et al., 2001; Aksenov et al., 2003; Buscemi et al., 2007; Eugenin et al., 2007). No statistically significant increases in neuronal cell death were observed with either mutant TatΔ31–61 or PBS, consistent with previous reports that this deletion mutant of Tat is not directly toxic to neurons (Buscemi et al., 2007).


Role of endolysosomes in HIV-1 Tat-induced neurotoxicity.

Hui L, Chen X, Haughey NJ, Geiger JD - ASN Neuro (2012)

HIV-1 Tat-induced neuronal cell death in a time-dependent mannerSignificant amounts of neuronal cell death were observed after 2-day incubation with HIV-1 Tat (100 nM) and reached a maximal level of 50% cell death by the fourth day. No significant neuronal cell death was observed in neurons treated with either mutant Tat or PBS (n = 5, *P<0.05 and ***P<0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3379000&req=5

Figure 1: HIV-1 Tat-induced neuronal cell death in a time-dependent mannerSignificant amounts of neuronal cell death were observed after 2-day incubation with HIV-1 Tat (100 nM) and reached a maximal level of 50% cell death by the fourth day. No significant neuronal cell death was observed in neurons treated with either mutant Tat or PBS (n = 5, *P<0.05 and ***P<0.001).
Mentions: In order to compare the effects of HIV-1 Tat on neuronal damage and the structure and function of endolysosomes, we needed to first determine the time course and extent to which HIV-1 Tat decreased neuronal viability. HIV-1 Tat1–72 induced significant amounts of neuronal cell death starting from 48 h of treatment (n = 5, P<0.05) with a maximum of 50% neuronal cell death (n = 5, P<0.001) after the treatment for 96 h (Figure 1). These data were consistent with previous studies that have shown similar neurotoxic effects of HIV-1 Tat (Kruman et al., 1998; Haughey et al., 1999; Bonavia et al., 2001; Aksenov et al., 2003; Buscemi et al., 2007; Eugenin et al., 2007). No statistically significant increases in neuronal cell death were observed with either mutant TatΔ31–61 or PBS, consistent with previous reports that this deletion mutant of Tat is not directly toxic to neurons (Buscemi et al., 2007).

Bottom Line: Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder).As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy.In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.

ABSTRACT
Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder). Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription) protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND.

Show MeSH
Related in: MedlinePlus