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HIV-1 Tat endocytosis and retention in endolysosomes affects HIV-1 Tat-induced LTR transactivation in astrocytes
- Source :
- FASEB J
- Publication Year :
- 2022
-
Abstract
- The presence of latent HIV-1 reservoirs in the periphery and brain represents a major obstacle to curing HIV-1 infection. As an essential protein for HIV-1 viral replication, HIV-1 Tat, mostly intracellular, has been implicated in latent HIV-1 infection. From HIV-1 infected cells, HIV-1 Tat is actively secreted and bystander cells uptake the released Tat whereupon it is endocytosed and internalized into endolysosomes. However, to activate the HIV-1 LTR promoter and increase HIV-1 replication, HIV-1 Tat must first escape from the endolysosomes and then enter the nucleus. Here, we tested the hypothesis that HIV-1 Tat can accumulate in endolysosomes and contribute to the activation of latent HIV-1 in astrocytes. Using U87MG astrocytoma cells expressing HIV-1 LTR-driven luciferase and primary human astrocytes we found that exogenous HIV-1 Tat enters endolysosomes, resides in endolysosomes for extended periods of time, and induces endolysosome de-acidification as well as enlargement. The weak base chloroquine promoted the release of HIV-1 Tat from endolysosomes and induced HIV-1 LTR transactivation. Similar results were observed by activating endolysosome Toll-like receptor 3 (TLR3) and TLR7/8. Conversely, pharmacological block of TLRs and knocking down expression levels of TLR3 and TLR7, but not TLR8, prevented endolysosome leakage and attenuated HIV-1 Tat-mediated HIV-1 LTR transactivation. Our findings suggest that HIV-1 Tat accumulation in endolysosomes may play an important role in controlling HIV-1 transactivation.
- Subjects :
- Gene Expression Regulation, Viral
Transcriptional Activation
HIV Infections
Endosomes
Virus Replication
Biochemistry
Article
Endocytosis
Virus Latency
Astrocytes
Cell Line, Tumor
Genetics
HIV-1
Humans
tat Gene Products, Human Immunodeficiency Virus
Lysosomes
Promoter Regions, Genetic
Molecular Biology
Biotechnology
HIV Long Terminal Repeat
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- FASEB J
- Accession number :
- edsair.doi.dedup.....99091ec2f0711326080a803e84bdb1fa