Role of Endolysosomes in HIV-1 Tat-Induced Neurotoxicity

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.

HIV-1-Tat excites cardiac parasympathetic neurons of nucleus ambiguus and triggers prolonged bradycardia in conscious rats

“…Tat has been reported to promote IP 3 formation and/or IP 3 R-mediated Ca 2ϩ mobilization from the endoplasmic reticulum in human fetal neurons and astrocytes (29), human macrophages (37), and human cerebrocortical terminals (23). Our finding that Tat mobilizes lysosomal Ca 2ϩ stores correlates well with the fact that this protein enters neurons rapidly via receptor-mediated endocytosis, altering the endolysosomal structure and function (15,30). Since TRPV 2 are Ca 2ϩ -permeable nonselective cation channels modulated by Ca 2ϩ and by phosphatidylinositol-4,5-bisphosphate metabolism (39,42), we propose that HIV Tat acts first to mobilize intracellular Ca 2ϩ stores and that TRPV 2 stimulation occurs consequently (Fig.…”

Role of autophagy in HIV infection and pathogenesis

“…Neurons may be targeted by both systemic circulating TAT crossing the blood-brain barrier and TAT released from infected glial cells [82]. Consistent with this possibility, TAT has been detected in the brain of patients with HIV-associated dementia [84,85].…”

“…It is important to note that some of the effects of TAT on autophagy may be indirect, as it is also able to interfere with the endo-lysosomal compartment, by increasing luminal pH and compromising membrane integrity [84]. A recent detailed study of the effect of TAT on autophagy showed that treatments both in vitro and in GFAP-TAT transgenic mice induce accumulation of abnormal neuronal autophagosomes, suggesting that TAT alters the fusion of autophagosomes with lysosomes [80].…”

Cocaine-mediated microglial activation involves the ER stress-autophagy axis

“…59,60 Interestingly HIV proteins such as transactivator of transcription (Tat) and the envelope protein gp120 have also been implicated to independently regulate autophagic pathways. 61 activation. 63,64 Cocaine can thus accelerate the incidence and progression of (HIV)-1 associated neurological disorders via exacerbation of the autophagy-mediated microglial activation response.…”