HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.

HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.:

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HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.

Glia. 2020 Apr 06;:

Authors: Proust A, Barat C, Leboeuf M, Drouin J, Gagnon MT, Vanasse F, Tremblay MJ

Abstract

Since the introduction of the combined antiretroviral therapy, HIV-1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age-related pathologies such as neurocognitive disorders have emerged as serious complications. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV-1-infected brains, we investigated the consequences of HIV-1 infection and treatment with two LRA (bryostatin-1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV-1-infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin-1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ-loaded microvesicles. Thus, both HIV-1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV-1-infected persons.

PMID: 32250524 [PubMed - as supplied by publisher]