HIV NEUROTOXICITY: HOW TAT PROTEIN CAN DAMAGE THE CNS THROUGH MICRORNA

OTAVIO E SILVA RODRIGUES FILHO, JULIANA VIEIRA BITANTE FREITAS, FAUSI PADILHA GONÇALVES, EDWARD ZIFF, ELISABETE CASTELON KONKIEWITZ

Resumo


Introduction: Although CART drugs are effective in the AIDS treatment, their low efficacy to penetrate the
CNS and the tropism of HIV by this system explains a prevalence of about 70% of HIV patients with a
complaint of neurological disorder1 that can range from sensory-motor disorders to depression and
dementia2. There are several mechanisms by which the virus injuries CNS and, although not everyone is
fully elucidated, those assigned to Tat protein sources are of great interest. Some studies trying to
understand the complex mechanisms involved in the HIV-induced neurotoxicity associates the Tat Protein
with microRNA’s (miRNA's), which are a kind of post-transcriptional regulators discovered just over a
decade3. This review will discuss some ways in which Tat damages the CNS through changes in the
expression of different miRNA's. Objectives: Demonstrate neurotoxic mechanisms promoted by Tat
through miRNA's. Material and Methods: Literacture review of articles published in PubMed and Scielo
databases, with a maximum of five years of publication, using older articles or different databases only
when essential for the development of research. Results: Microglia lesions induction: An Indian
experiment4 demonstrated that Tat decreases the expression of miR-17, bringing as result increased levels
of NOX-2 and NOX-4 electron carriers, and thus increasing intracellular levels of Reactive Oxygen Species
(ROS). ROS are connected to inflammatory cytokines production5. Another Indian research6 showed that
the induction of miR-32 by Tat decreases the production of TRAF3 protein, compromising the immune
signaling, thereby decreasing the local immune response. Blood-Brain Barrier (BBB) increased
permeability: BBB efficiency is compromised by increased expression of miR-101, which reduces the
endothelial adhesion molecules expression, more specifically VE-cadherin and claudin-57. Synaptic
degeneration: Neurotransmission is impacted when Tat induces overexpression of miR-128, which in turn
decreases the SNAP25 protein production8, who plays an important role in exocytosis9. Synaptic
degeneration is a common signal and factor to many types of dementia, including the HIV-Associated
Dementia (HAD). CONCLUSIONS: We could identified at least four different mechanisms in which Tat
protein, through changes in miRNA's expression, promotes CNS injuries. Understand the
pathophysiological aspects of diseases is primordial to fight against them. In the miRNA's case, their
biologic potentials are source of large scientific interest. Talking about HIV neurological disorders,
specifically induced by Tat, the knowledge of how that protein alters the expression of miRNA's may be a
potential target for new therapeutic techniques or development of new drugs who may reduces the
neurotoxic effects of HIV, thereby improving life quality of patients.

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